Cycloalkane Carboxamide Derivatives and Production Process of Same

ABSTRACT

Novel cycloalkane carboxamide derivatives having an action that selectively inhibits cathepsin K, and a production process thereof, are provided. 
     A cycloalkane carboxamide derivative represented by the following general formula (I), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     (wherein R 1  and R 2  represent (substituted) alkyl groups, (substituted) alkenyl groups, (substituted) alkynyl groups, (substituted) aromatic hydrocarbon groups or (substituted) heterocyclic groups, ring A represents an alkylidene group having 5 to 7 carbon atoms, and ring B represents a formyl group or a hydroxymethyl group).

TECHNICAL FIELD

The present invention relates to novel cycloalkane carboxamidederivatives and a production process thereof. More particularly, thepresent invention relates to cycloalkane carboxamide derivatives havingthe action of selectively inhibiting cathepsin K which is the maincysteine protease involved in bone resorption, and to a productionprocess thereof.

BACKGROUND ART

Accompanying the rapid progression to an elderly society in recentyears, the number of patients with geriatric diseases, and particularlythose with bone diseases, is continuing to increase. In particular,osteoporosis, which is prevalent among women and especiallypostmenopausal women, is becoming a serious problem. Since acceleratedbone resorption brought about by a loss of hormonal balance and agingphenomena in postmenopausal women is intimately related to the onset andprogression of bone disease, bone resorption inhibitors have been usedduring the course of ordinary drug therapy for osteoporosis. However,drugs currently in use that demonstrate bone resorption inhibitoryaction, such as calcitonin preparations, estrogen preparations, vitaminK preparations and bisphosphonate preparations, have problems in termsof their therapeutic effects, rapid-acting, adverse side effects andpatient compliance, thus desiring the development of a bone resorptioninhibitor capable of being used as a more effective drug for thetreatment or prevention of osteoporosis.

In the living body, bone calcium concentrations and blood calciumconcentrations are in a state of equilibrium, and calcium is constantlymigrating between the bone and blood. This migration of calcium isgoverned by dynamic shifts between bone formation and bone resorption.In the process of bone resorption, bone resorption is known to beaccelerated as a result of activated osteoclasts eluting bone inorganicsubstances such as calcium simultaneous to cysteine proteases secretedfrom osteoclasts decomposing bone organic substances such as collagen.Cysteine proteases such as cathepsin B, cathepsin H, cathepsin L andcathepsin S are present in osteoclast lysosomes, andosteoclast-localized human cathepsin K was isolated in 1995, which wasdemonstrated to be expressed in osteoclasts in larger amounts than othercathepsins (Biochem. Biophys. Res. Commun., 206, 89 (1995); J. Biol.Chem., 271, 12511 (1996)). Moreover, the cathepsin K gene wasdemonstrated to mutate in patients with dwarfism presenting with boneresorption abnormalities (Science, 273, 1236 (1997)).

In this manner, attention has been focused on cathepsin K as the maincysteine protease involved in bone resorption, and considerableexpectations are being placed on cathepsin K inhibitors as inhibitors ofbone resorption. Previously reported examples of compounds havingcathepsin K inhibitory action include aldehyde derivatives, epoxysuccinic acid derivatives (J. Biol. Chem., 271, p. 2126 (1996); Biol.Pharm. Bull., 19, p. 1026 (1996)) and vinylsulfonic acid derivatives(Nature Structural Biology, 4, p. 105 (1997); J. Med. Chem., 38, p. 3139(1995)), and these derivatives have low selectivity and are known tostrongly inhibit other cysteine proteases in addition to cathepsin K (J.Enzyme Inhibition, 3, p. 13 (1989); Biochem. Biophys. Res. Commun., 153,p. 1201 (1988); J. Biochem., 87, p. 39 (1980); J. Biochem., 88, p. 805(1980)).

Moreover, accompanying the growing interest in cathepsin K as describedabove, research has also been actively conducted in the area of X-raycrystal analyses of cathepsin K and inhibitors (Nature StructuralBiology, 4, p. 105 (1997); Nature Structural Biology, 4, p. 109 (1997)),and compounds are known that has a selective inhibitory action oncathepsin K (Proc. Natl. Acad. Sci. USA, 94, 142, p. 49 (1997);WO9801133; J. Am. Chem. Soc., 120, 9, p. 114 (1998); J. Med. Chem., 41,p. 3563 (1988); Japanese Unexamined Patent Publication No. 2000-204071;Bioorg. Med. Chem., 14, p. 4333 (2004); Bioorg. Med. Chem., 14, p. 4897(2004)). In addition, WO971677 identifies the catalyst active site ofcathepsin K and discloses a method for inhibiting cathepsin K using acompound that interacts with this active site.

Moreover, although not containing descriptions of inhibition ofcathepsin K, Japanese Unexamined Patent Publication Nos. Hei 2-256654and Hei 2-268145 disclose various types of aldehyde derivatives asprotease inhibitors.

[Non-patent document 1] Proc. Natl. Acad. Sci. USA., 94, 142, p. 49(1997)

[Non-patent document 2] J. Am. Chem. Soc., 120. 9. p. 114 (1998)

[Non-patent document 3] J. Med. Chem., 41, p. 3563 (1998)

[Non-patent document 4] Bioorg. Med. Chem., 14, p. 4333 (2004)

[Non-patent document 5] Bioorg. Med. Chem., 14, p. 4897 (2004))

[Patent document 1] WO9801133

[Patent document 2] WO971677

[Patent document 3] Japanese Unexamined Patent Publication No.2000-204071

[Patent document 4] Japanese Unexamined Patent Publication No. Hei2-256654

[Patent document 5] Japanese Unexamined Patent Publication No. Hei2-268145

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

As has been described above, compounds that inhibit cathepsin K haveattracted attention as bone resorption inhibitors, and although numerousderivatives have been reported, none has yet been able to be usedpractically as a therapeutic drug for metabolic bone diseases. As aresult of extensive studies on novel compounds having potent andselective cathepsin K inhibitory action, the inventors of the presentinvention found that novel cycloalkane carboxamide derivativesrepresented by a specific structural formula selectively inhibitcathepsin K as compared with conventional aldehyde derivatives known tobe protease inhibitors.

An object of the present invention is to provide these novel cycloalkanecarboxamide derivatives and a production process thereof.

Means for Solving the Problems

The present invention is based on the fact that cycloalkane carboxamidederivatives represented by general formula (I) having anon-naturally-occurring amino acid structure selectively inhibitcathepsin K as compared with conventional aldehyde derivatives, relatesto compounds having more highly selective cathepsin K inhibitory actionand a production process thereof, and the gist thereof lies in thecycloalkane carboxamide derivatives described in 1 to 11 below and aproduction process thereof.

1. A cycloalkane carboxamide derivative represented by formula (I):

[wherein R¹ represents a substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon group,substituted or unsubstituted heterocyclic group, group represented byR⁴O—, group represented by R⁵S-(wherein R⁴ and R⁵ respectively andindependently represent a substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon group,or substituted or unsubstituted heterocyclic group), or grouprepresented by R⁶(R⁷)N-(wherein R⁶ and R⁷ respectively and independentlyrepresent a hydrogen atom, a substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon groupor substituted or unsubstituted heterocyclic group, furthermore R⁶ andR⁷ may together form a ring); R² represents a substituted orunsubstituted alkyl group, substituted or unsubstituted alkenyl group,substituted or unsubstituted alkynyl group, substituted or unsubstitutedaromatic hydrocarbon group, or substituted or unsubstituted heterocyclicgroup; ring A represents a cyclic alkylidene group having 5, 6 or 7carbon atoms; and B represents a formyl group or hydroxymethyl group;provided that in the case B is a formyl group, R² is not a2-carboxyethyl group] or a pharmaceutically acceptable salt thereof.2. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in 1 above, wherein alkyl groups in the groupsrepresented by R¹, R², R⁴, R⁵, R⁶ and R⁷ in the formula (I) are linear,branched or cyclic alkyl groups having 1 to 12 carbon atoms, the alkenylgroups are linear, branched or cyclic alkenyl groups having 2 to 12carbon atoms, the alkynyl groups are linear, branched or cyclic alkynylgroups having 2 to 12 carbon atoms, the aromatic hydrocarbon groups aremonocyclic or polycyclic aromatic hydrocarbon groups having 6 to 18carbon atoms, and the heterocyclic groups are heterocyclic groups of 3-to 7-membered rings containing at least one nitrogen atom, oxygen atomor sulfur atom as a ring-constituting atom.3. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in 1 or 2 above, wherein substituents of thealkyl groups in the groups represented by R¹, R², R⁴, R⁵, R⁶ and R⁷ inthe formula (I) are a group selected from a hydroxyl group, alkenylgroup, alkynyl group, halogen atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup and Rx(Ry)N group (wherein Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group); andsubstituents of the alkenyl groups, alkynyl groups, aromatic hydrocarbongroups and heterocyclic groups are a group selected from a hydroxylgroup, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatichydrocarbon group, heterocyclic group, alkoxy group, guanidino group,alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group,acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthiogroup, amido group, ureido group, carboxyl group, carbamoyl group, oxogroup, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxygroup, azido group, sulfonamido group, mercapto group,alkoxycarbonylamino group and Rx(Ry)N group (wherein Rx and Ryrespectively and independently represent a hydrogen atom, alkyl group,alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclicgroup).4. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 1 to 3 above, wherein B in the formula(I) is a hydroxymethyl group.5. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 1 to 3 above, wherein B in the formula(I) is a formyl group.6. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 1 to 5 above, wherein R¹ in the formula(I) is a substituted or unsubstituted alkyl group, substituted orunsubstituted alkenyl group, substituted or unsubstituted aromatichydrocarbon group, or substituted or unsubstituted heterocyclic group,and R¹ is a substituted or unsubstituted alkyl group, or substituted orunsubstituted aromatic hydrocarbon group.7. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 1 to 4 above, wherein the substitutedor unsubstituted alkyl group, substituted or unsubstituted alkenylgroup, substituted or unsubstituted alkynyl group, substituted orunsubstituted aromatic hydrocarbon group, or substituted orunsubstituted heterocyclic group represented by R² in the formula (I) isa group derived from an α-amino acid, and the α-amino acid is an α-aminoacid selected from alanine, arginine, asparagine, aspartic acid,isoasparagine, γ-carboxyglutamic acid, cysteine, cystine, glutamine,glutamic acid, histidine, homoarginine, homocysteine, homocystine,homoserine, homophenylalanine, isoleucine, leucine, lysine, methionine,norleucine, t-leucine, norvaline, ornithine, phenylalanine,phenylglycine, serine, threonine, tryptophan, tyrosine, valine,3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine,allothreonine, homolysine, naphthylalanine, α-aminoadipic acid,thienylglycine, pyridylalanine and cyclohexylalanine.8. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 1, 2, 3 and 5 above, wherein thesubstituted or unsubstituted alkyl group, substituted or unsubstitutedalkenyl group, substituted or unsubstituted alkynyl group, substitutedor unsubstituted aromatic hydrocarbon group, or substituted orunsubstituted heterocyclic group represented by R² in the formula (I) isa group derived from an α-amino acid, and the α-amino acid is an α-aminoacid selected from alanine, arginine, asparagine, aspartic acid,isoasparagine, γ-carboxyglutamic acid, cysteine, cystine, glutamine,histidine, homoarginine, homocysteine, homocystine, homoserine,homophenylalanine, isoleucine, leucine, lysine, methionine, norleucine,norvaline, ornithine, phenylalanine, phenylglycine, serine, threonine,tryptophan, tyrosine, valine, 3,4-dihydroxyphenylalanine, allylglycine,neopentylglycine, allothreonine, homolysine, naphthylalanine,α-aminoadipic acid, thienylglycine, pyridylalanine andcyclohexylalanine.9. The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof described in any of 4 to 8 above, wherein R¹ in the formula(I) is a 3- to 7-membered substituted or unsubstituted heterocyclicgroup, containing at least one nitrogen atom, oxygen atom or sulfur atomas a ring-constituting atom, or a substituted aromatic hydrocarbongroup, R² is an alkyl group having 1 to 4 carbon atoms and ring A is acyclohexylidene group.10. A process for producing a cycloalkylcarbonylamino aldehydederivative represented by the following formula (XIII) by oxidizing acycloalkylcarbonylamino alcohol derivative represented by the followingformula (XI):

(wherein ring A, R¹ and R² in the formulas (XI) and (XIII) are the sameas previously defined in 1 above).11. A process for producing a cycloalkylcarbonylamino alcohol derivativerepresented by the following formula (XI) from an oxazolone derivativerepresented by the following formula (I_(o)) according to any of thefollowing steps (A) to (C):

Step (A):

an oxazolone derivative represented by formula (I_(o)) is reacted withan amino acid derivative represented by formula (VII) to form acycloalkylcarbonylamino acid derivative represented by formula (X), andthe cycloalkylcarbonylamino acid derivative is followed by reduction;

Step (B):

an oxazolone derivative represented by formula (I_(o)) is reacted withan amino acid ester derivative represented by formula (IX) to form acycloalkylcarbonylamino acid ester derivative represented by formula(XII), and the cycloalkylcarbonylamino acid ester derivative is followedby reduction;

Step (C):

an oxazolone derivative represented by formula (I_(o)) is condensed withan amino alcohol derivative represented by formula (VIII);

(wherein R¹, R² and ring A in the formulas (I_(o)), (VII), (VIII) (IX),(X), (XI) and (XII) above are the same as previously defined in 1 above,and R⁸ in formulas (IX) and (XII) represents a substituted orunsubstituted alkyl group having 1 to 6 carbon atoms).

EFFECTS OF THE INVENTION

The novel cycloalkane carboxamide derivatives of the present inventionhave highly active and highly selective cathepsin K inhibitory activity.Thus, compounds of the present invention are useful in the preventionand treatment of such diseases as osteoporosis, hypercalcemia, Paget'sdisease, bone resorption diseases, osteogenesis imperfecta,osteoarthrosis, rheumatoid arthritis, arthritis, Klinefelter's syndrome,hereditary hyperphosphatasemia, Charcot's neuroarthopathy, mastocytosis,Gaucher's disease, cancer metastasis and multiple myeloma, and thecontribution thereof to the medical care of these diseases isconsiderable.

BEST MODE FOR CARRYING OUT THE INVENTION

The cycloalkane carboxamide derivatives of the present invention arecompounds represented by the aforementioned formula (I) andpharmaceutically acceptable salts thereof, and specific examples ofalkyl groups, alkenyl groups, alkynyl groups, aromatic hydrocarbongroups and heterocyclic groups included by the groups represented bysubstituents R¹, R², R⁴, R⁵, R⁶ and R⁷ in these derivatives are listedbelow.

The alkyl group may be any of a linear, branched and cyclic alkyl grouphaving 1 to 12 carbon atoms, examples of which include a methyl group,ethyl group, n-propyl group, 2-propyl group, cyclopropyl group, n-butylgroup, 2-methylpropyl group, 2-butyl group, 1,1-dimethylethyl group,cyclobutyl group, n-pentyl group, 3-methylbutyl group, cyclopentylgroup, 2,2-dimethylpropyl group, 1-methylcyclobutyl group,cyclobutylmethyl group, n-hexyl group, 4-methylpentyl group, cyclohexylgroup, 1-methylcyclopentyl group, cyclopentylmethyl group,(1-methylcyclobutyl)methyl group, n-heptyl group, 5-methylhexyl group,4,4-dimethylpentyl group, cycloheptyl group, cyclohexylmethyl group,(1-methylcyclopentyl)methyl group, n-octyl group, 6-methylheptyl group,5,5-dimethylhexyl group, (1-methylcyclohexyl)methyl group, n-nonylgroup, 7-methyloctyl group, 6,6-dimethylheptyl group, n-decyl group,8-methylnonyl group, n-dodecacyl group, 10-methylundecacyl group and9,9-dimethyldecacyl group.

The alkenyl group may be any of a linear, branched and cyclic alkenylgroup having 2 to 12 carbon atoms, examples of which include a vinylgroup, 1-propenyl group, 2-propenyl group, 1-methylethenyl group,1-methyl-1-propenyl group, 1-methyl-2-propenyl group,2-methyl-2-propenyl group, 1-propenyl group, 2-propenyl group, 1-butenylgroup, 2-butenyl group, 2-pentenyl group, 1-pentenyl group, 1-hexenylgroup and 2-hexenyl group.

The alkynyl group may be any of a linear, branched and cyclic grouphaving 2 to 12 carbon atoms and may be substituted, examples of whichinclude an ethynyl group, 1-propynyl group, 2-propynyl group and2-butynyl group.

The aromatic hydrocarbon group may be a monocyclic or polycyclic grouphaving 6 to 18 carbon atoms, examples of which include a phenyl group,naphthyl group and anthranyl group.

The heterocyclic group is a 3- to 7-membered ring group containing atleast one heteroatom such as a nitrogen atom, oxygen atom or sulfur atomas a ring-constituting atom, and these may condense heterocyclic groups,aliphatic rings or aromatic rings or form a spiro ring, examples ofwhich include a furanyl group, thienyl group, pyrrolyl group, pyrazolylgroup, thiazolyl group, oxazolyl group, isoxazolyl group, pyridinylgroup, pirazinyl group, pyrimidinyl group, pyridazinyl group, pyranylgroup, indolyl group, benzofuranyl group, benzimidazolyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, pyrrolidinylgroup, piperidinyl group, piperazinyl group, morpholinyl group,indolinyl group and benzodioxolyl group. It is preferably a furanylgroup or morpholinyl group.

However, in the case B is a formyl group in the formula (I), R² is not a2-carboxyethyl group.

In addition, examples of substituents able to be possessed by the alkylgroups include groups selected from a hydroxyl group, alkenyl group,alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclicgroup, alkoxy group, guanidino group, alkylthio group, alkoxycarbonylgroup, aryloxy group, arylthio group, acyl group, sulfonyl group,heterocyclyloxy group, heterocyclylthio group, amido group, ureidogroup, carboxyl group, carbamoyl group, oxo group, sulfamoyl group,sulfo group, cyano group, nitro group, acyloxy group, azido group,sulfonamido group, mercapto group, alkoxycarbonylamino group and anRx(Ry)N group (wherein Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group).

Moreover, examples of substituents able to be possessed by the alkenylgroups, alkynyl groups, aromatic hydrocarbon groups and heterocyclicgroups include groups selected from a hydroxyl group, alkyl group,alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup and an Rx(Ry)N group (wherein Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group).

Furthermore, the alkyl groups, alkenyl groups, alkynyl groups, aromatichydrocarbon groups and heterocyclic groups listed as examples of Rx, Ryand substituents include the same types of groups as the groupsrepresented by R¹, R², R⁴, R⁵, R⁶ and R⁷. In addition, the alkyl groupsof alkoxy groups, alkylthio groups as the substituents, alkoxycarbonylgroups and alkoxycarbonylamino groups are also the same as thepreviously described alkyl groups having 1 to 12 carbon atoms, and thearyl groups of aryloxy groups and arylthio groups are also the same asthe previously described aromatic hydrocarbon groups having 6 to 18carbon atoms. In addition, examples of the guanidino groups, acylgroups, sulfonyl groups, heterocyclyloxy groups, heterocyclylthiogroups, amido groups, ureido groups, carbamoyl groups, sulfamoyl groups,acyloxy groups, sulfonamido groups and alkoxycarbonylamino groups as thesubstituents are indicated below.

(In the examples of groups indicated above, R⁹ to R¹², R¹⁷ to R²¹, R²³to R²⁵, R²⁸ and R³⁰ represent hydrogen atoms, substituted orunsubstituted alkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, substituted orunsubstituted aromatic hydrocarbon groups or substituted orunsubstituted heterocyclic groups. R¹³, R¹⁴, R²², R²⁶, R²⁷ and R²⁹represent substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted aromatic hydrocarbon groups orsubstituted or unsubstituted heterocyclic groups. R¹⁵ and R¹⁶ representsubstituted or unsubstituted heterocyclic groups. In addition, examplesof substituents of these substituted alkyl groups, substituted alkenylgroups, substituted alkynyl groups, substituted aromatic hydrocarbongroups and substituted heterocyclic groups include the same groups asthe substituents of these groups listed for R¹ in 3 above.)

In the cycloalkane carboxamide derivatives represented by formula (I) ofthe present invention, ring A is a cyclopentylidene group,cyclohexylidene group or cycloheptylidene group, and preferably acyclohexylidene group.

In formula (I), a compound wherein R¹ is a 3- to 7-membered ringheterocyclic group containing at least one nitrogen atom, oxygen atom orsulfur atom as a ring-constituting group, or a substituted aromatichydrocarbon group, R² is an alkyl group having 1 to 4 carbon atoms, andring A is a cyclohexylidene group is preferable.

In the case a cycloalkane carboxamide derivative represented by formula(I) of the present invention has a basic site in a molecule thereof, asalt can be formed with an inorganic acid or organic acid, and examplesof inorganic acids include hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and hydrobromic acid. Examples of organic acidsinclude acetic acid, propionic acid, benzoic acid, oxalic acid, malonicacid, succinic acid, phthalic acid, glycolic acid, lactic acid, glycericacid, malic acid, tartaric acid, gallic acid, citric acid, maleic acid,fumaric acid, methanesulfonic acid, benzenesulfonic acid andtoluenesulfonic acid.

Moreover, in the case the cycloalkane carboxamide derivative has anacidic site in a molecule thereof, a salt can be formed with, forexample, an alkali metal such as lithium, sodium or potassium, analkaline earth metal such as magnesium or calcium, aluminum or zinc. Inaddition, a salt can also be formed with an organic base, and examplesof such an organic base include primary amines such as methylamine,ethylamine or aniline, secondary amines such as diethylamine,pyrrolidine, piperidine, morpholine, piperazine or dicyclohexylamine,tertiary amines such as trimethylamine, triethylamine,N,N-diisopropylethylamine or pyridine, and ammonia.

The following indicates an example of the production of a cycloalkanecarboxamide derivative represented by formula (I) of the presentinvention.

(In the above formulas, R¹, R² and ring A are the same as previouslydefined in the formula (I), R³ and R⁸ represent substituted orunsubstituted alkyl groups having 1 to 6 carbon atoms, and X representsa hydroxyl group or a leaving group.)

Step 1:

This step is a step for producing a cycloalkylcarboxylic acid derivativerepresented by formula (VI) above by condensing an amino acidrepresented by formula (II) above with a carboxylic acid or carboxylicacid derivative represented by formula (IV) above. As carboxylic acidderivatives, for example, acid halides, active esters and acidanhydrides can be used. In addition, in this step, reaction can becarried out by adding a base as necessary. As bases, for example,pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, sodium carbonate,potassium carbonate, sodium hydrogencarbonate, sodium hydroxide andpotassium hydroxide can be used.

When this step is carried out, it is preferably carried out in asolvent, and organic solvents such as methylene chloride, chloroform,dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethylether, isopropyl ether or dimethoxyethane, and water can be used. Amixed solvent of an organic solvent and water can be used as necessary.The reaction is normally carried out at a reaction temperature withinthe range of −30 to 200° C. and is preferably allowed to proceed withinthe range of −15 to 100° C.

Step 2:

This step is a step for producing a cycloalkyl ester derivativerepresented by formula (V) above by a condensation reaction between anamino acid ester represented by formula (III) above with a carboxylicacid or carboxylic acid derivative represented by formula (IV) above. Ascarboxylic acid derivatives, for example, acid halides, active esters oracid anhydrides can be used. In this step, the reaction can be carriedout by adding a condensation agent or base as necessary. As condensationagents, for example, dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride,diisopropylcarbodiimide and carbonyldiimidazole can be used. Here, anactivator such as 1-hydroxybenzotriazole can also be added as necessary.As bases, pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, sodium carbonate,potassium carbonate and sodium hydrogencarbonate can be used.

When this step is carried out, it is preferably carried out in asolvent, and organic solvents such as methylene chloride, chloroform,dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethylether, isopropyl ether or dimethoxyethane, and water can be used. Amixed solvent of an organic solvent and water can be used as necessary.The reaction is normally carried out at a reaction temperature withinthe range of −30 to 200° C. and is preferably allowed to proceed withinthe range of −15 to 100° C.

Step 3:

This step is a step for producing a compound of formula (VI) above by ahydrolysis reaction or a hydrogenation reaction by catalytic reductionusing a metal catalyst of the cycloalkyl ester derivative represented byformula (V) above. Hydrolysis can be carried out in the presence of anacid or base. As acids, for example, hydrochloric acid, sulfuric acid,nitric acid and acetic acid can be used. As bases, for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate andpotassium carbonate can be used. When this step is carried out, it ispreferably carried out in water or in a mixed solvent of an organicsolvent and water, and as organic solvents, for example, methanol,ethanol, isopropyl alcohol, tetrahydrofuran and dimethoxyethane can beused. The reaction is normally carried out at a reaction temperaturewithin the range of −20 to 200° C. and is preferably allowed to proceedwithin the range of 0 to 180° C. In addition, as metal catalysts in thecatalytic hydrogenation reaction, for example, platinum, palladium,nickel, rhodium, ruthenium and copper can be used. When this step iscarried out, it is preferably carried out in a solvent, and methanol,ethanol, isopropyl alcohol, isopropyl ether, tetrahydrofuran, benzene,toluene, xylene, dimethylformamide, dioxane and water can be used, forexample. The reaction is normally carried out at a reaction temperatureof −50 to 200° C. and is preferably allowed to proceed within the rangeof 10 to 100° C.

Examples of the carboxylic acid or carboxylic acid derivativerepresented by formula (IV) above include the compounds listed below.

Carboxylic acids: acetic acid, isobutyric acid, acrylic acid, propionicacid, cyclohexanecarboxylic acid, benzoic acid, cinnamic acid,2-furancarboxylic acid, nicotinic acid, tetrahydrofuran-2-carboxylicacid, 1-acetyl-piperidine-2-carboxylic acid, 2-pyrrolecarboxylic acid,5-indolecarboxylic acid;

acid halides: acetyl chloride, benzoyl chloride, pivaloyl chloride,2-furancarbonyl chloride, 4-morpholinecarbonyl chloride,2-thiophenecarbonyl chloride;

active esters: 1-acetylimidazole, benzoic acid p-nitrophenyl esters,benzoic acid N-hydroxysuccinimide esters, benzoic acid1-hydroxybenzotriazole esters; and

acid anhydrides: acid anhydrides of benzoic acid and methyl carbonate,acid anhydrides of benzoic acid and isobutyl carbonate, acid anhydridesof benzoic acid and pivalic acid, acid anhydrides of benzoic acid andmethanesulfonic acid.

The cycloalkylcarboxylic acid derivatives represented by formula (VI)above include, for example, the compounds listed below:

-   1-[(phenylacetyl)amino]cyclohexanecarboxylic acid,    1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylic acid,    1-(benzoylamino)cyclohexanecarboxylic acid,    1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(1-naphthylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[[(RS)-2,3-tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylic    acid, 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic    acid, 1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylic acid,-   1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic    acid, 1-[(2-thienylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(2-pyridinylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(3-ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid,    1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(3-methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[(3-pyridinylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic    acid, 1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid,    1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid,-   1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(4-pyridinylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(6-hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[(2-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic    acid, 1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid,    1-[[(2-oxo-2H-pyran-5-yl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid hydrochloride,-   [[(2,3-dihydro-2-oxo-5-benzoxazole)carbonyl]amino]cyclohexanecarboxylic    acid,    [[(2,3-dihydro-1,4-benzodioxin-6-yl)carbonyl]amino]cyclohexanecarboxylic    acid,    [[(2,4-dioxo-3-thiazolidinyl)acetyl]amino]cyclohexanecarboxylic    acid, [(1-oxo-3-phenyl-2-propenyl)amino]cyclohexanecarboxylic acid,    [[1-oxo-3-(2-chlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-chlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dichlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-bromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-bromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dibromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[(1-oxo-3-(2-fluorophenyl)-2-propenyl)amino]cyclohexanecarboxylic    acid,-   [[1-oxo-3-(2-iodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(4-fluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(difluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-iodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(diiodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(trifluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(3-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,-   [[1-oxo-3-(dimethylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-methoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-methoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dimethoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(nitrophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dinitrophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(acetaminophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(2-pyridinyl)-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-cyclohexyl-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-cyclopentyl-2-propenyl]amino]cyclohexanecarboxylic    acid, [(1-oxo-3-phenyl-2-propynyl)amino]cyclohexanecarboxylic acid,    [[1-oxo-3-(fluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(chlorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(bromophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(iodophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,-   [[1-oxo-3-(difluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dibromophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(diiodophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(trifluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid, [(1-oxo-3-cyclohexyl-2-propynyl)amino]cyclohexanecarboxylic    acid, [(1-oxo-3-cyclopentyl-2-propynyl)amino]cyclohexanecarboxylic    acid, [[3-(2-furanyl)-1-oxo-2-propynyl]amino]cyclohexanecarboxylic    acid,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid acetate,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid hydrobromide,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid benzensulfonate,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid toluenesulfonate,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid phtalate,    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid fumarate, and    1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic    acid citrate.

Step 4:

This step is a step for producing an oxazolone derivative represented byformula (I_(o)) above by ring-closing the cycloalkylcarboxylic acidderivative represented by formula (VI) above by a dehydration reaction.The dehydration reaction of this step is preferably carried out in thepresence of a condensation agent, halogenating agent, acid, acidanhydride, acid chloride and the like, and as condensation agents,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide and carbonyldiimidazole can beused. As halogenating agents, for example, chlorine, bromine, iodine,phosphorous pentachloride, thionyl chloride, oxalyl chloride and thionylbromide can be used. As acids, for example, acetic acid, sulfuric acid,hydrochloric acid, methanesulfonic acid and toluenesulfonic acid can beused. As acid anhydrides, for example, acetic anhydride, methanesulfonicanhydride, toluenesulfonic anhydride and trifluoromethanesulfonicanhydride can be used. As acid chlorides, for example, acetyl chloride,pivaloyl chloride, methanesulfonyl chloride, toluenesulfonyl chloride,methyl chloroformate, ethyl chloroformate, propyl chloroformate andisobutyl chloroformate can be used.

In addition, the reaction of this step can also be carried out by addinga base as necessary, and as bases, for example, pyridine, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, sodium carbonate, potassium carbonate and sodiumhydrogencarbonate can be used.

When this step is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, ethylacetate, acetone, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl etherand dimethoxyethane can be used, for example. The reaction is normallycarried out at a reaction temperature within the range of −30 to 200° C.and is preferably allowed to proceed within the range of 0 to 100° C.

Step 5:

This step is a step for producing a cycloalkylcarbonyl-amino acidderivative represented by the formula (X) by reacting the oxazolonederivative represented by formula (I_(o)) above with the amino acidderivative represented by formula (VII) above.

This step can be carried out in the presence of a base and in thepresence or absence of a solvent, and as solvents, methylene chloride,chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene,xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane,diethyl ether, diisopropyl ether, dimethoxyethane, dimethyl sulfoxide,methanol, ethanol and 2-propanol can be used, for example. In addition,as bases, for example, pyridine, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, sodium hydroxide and potassium hydroxide can be used.The reaction is normally carried out at a reaction temperature withinthe range of −30 to 200° C. and can be preferably allowed to proceedwithin the range of 20 to 200° C.

The amino acid derivatives represented by formula (VII) above include,for example, the compounds listed below:

alanine, arginine, N^(ω)-nitro-arginine, asparagine, aspartic acid,β-benzyl ester, isoasparagine, γ-carboxyglutamic acid, cysteine,S-acetamido-cysteine, S-trityl-cysteine, cystine, glutamine, glutamicacid, glutaminic acid γ-t-butyl ester, histidine, homoarginine,homocysteine, homocystine, homoserine, homophenylalanine, isoleucine,leucine, t-leucine, lysine, N^(ε)-t-butoxycarbonyl-lysine, methionine,norleucine, norvaline, ornithine, N^(δ)-carbobenzoxy-ornithine,phenylalanine, phenylglycine, serine, O-benzyl-serine, threonine,O-t-butylthreonine, tryptophan, tyrosine, O-benzyl-tyrosine, valine,3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine,allothreonine, homolysine, naphthylalanine, α-aminoadipic acid,thienylglycine, pyridylalanine and cyclohexylalanine.

Step 6:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above. In this step, acycloalkylcarbonylamino alcohol derivative represented by formula (XI)above can be produced by two types of methods, namely a method that usesa cycloalkylcarboxylic acid derivative represented by formula (VI) abovefor the starting raw material (Step 6-A), and a method that uses anoxazolone derivative represented by formula (I_(o)) above for thestarting raw material (Step 6-B).

Step 6-A:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by condensing acycloalkylcarboxylic acid derivative represented by formula (VI) abovewith an amino alcohol derivative represented by formula (VIII) above.

As condensation agents in this step, for example,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide and carbonyldiimidazole can beused. Here, an activator such as 1-hydroxybenzotriazole orN-hydroxysuccinimide can be added as necessary.

In addition, this step can also be carried out by condensing in thepresence of a base according to a mixed acid anhydride method with anacid chloride. As acid chlorides, for example, pivaloyl chloride,isobutyl chloroformate, methyl chloroformate, ethyl chloroformate,methanesulfonyl chloride and toluenesulfonyl chloride can be used. Asbases, for example, pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine and N-methylmorpholine can be used.

When this step is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, ethylacetate, acetone, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl etherand dimethoxyethane can be used, for example.

The reaction is normally carried out at a reaction temperature withinthe range of −30 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 100° C.

Step 6-B:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by reacting an oxazolonederivative represented by formula (I_(o)) above with an amino alcoholderivative represented by formula (VIII) above.

This step can be carried out in the presence or absence of solvent, andas solvents, methylene chloride, chloroform, dichloroethane, ethylacetate, acetone, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropylether, dimethoxyethane, dimethyl sulfoxide, methanol, ethanol and2-propanol can be used, for example. In addition, in this step, a basecan be added as necessary. As bases, for example, pyridine,triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine andN-methylmorpholine can be used. The reaction is normally carried out ata reaction temperature within the range of −30 to 200° C. and can bepreferably allowed to proceed within the range of 20 to 200° C.

Amino alcohol derivatives represented by formula (VIII) above used instep 6, include, for example, the compounds listed below:

alaminol, N^(ω)-p-toluenesulfonyl-argininol,3-amino-4-hydroxybutanamide, 3-amino-4-hydroxybutanoic acid t-butylester, 3-benzylthio-2-aminopropanol, 4-amino-5-hydroxypentanamide,4-amino-5-hydroxypentanoic acid benzyl ester, histidinol, homoserinol,homophenylalaminol, isoleucinol, leucinol, t-leucinol,2-amino-6-[(t-butoxycarbonyl)amino]hexanol, methioninol, norleucinol,norvalinol, 2-amino-5-(dibenzylamino)pentanol, phenylalaminol,phenylglycinol, 2-amino-3-(benzyloxy)propanol, threoninol, tryptophanol,tyrosinol, valinol, 3,4-dihydroxyphenylalaminol, allylglycinol,neopentylglycinol, allothreoninol, naphthylalaminol, thienylglycinol,pyridylalaminol, cyclohexylalaminol, 2-amino-1-phenyl-1,3-propanediol,2-amino-1,3-propanediol and sphingosine.

Step 7:

This step is a step for producing a cycloalkylcarbonylamino acid esterderivative represented by formula (XII) above. In this step, acycloalkylcarbonylamino acid derivative represented by formula (XII)above can be produced by two types of methods, namely a method that usesa cycloalkylcarboxylic acid derivative represented by formula (VI) abovefor the starting raw material (Step 7-A), and a method that uses anoxazolone derivative represented by formula (I_(o)) above for thestarting raw material (Step 7-B).

Step 7-A:

This step is a step for producing a cycloalkylcarbonylamino acid esterderivative represented by formula (XII) above by condensing acycloalkylcarboxylic acid derivative represented by formula (VI) abovewith an amino acid ester derivative represented by formula (IX) above.

As condensation agents in this step, for example,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide and carbonyldiimidazole can beused. Here, an activator such as 1-hydroxybenzotriazole orN-hydroxysuccinimide can be added as necessary.

In addition, this step can also be carried out by condensing in thepresence of a base according to a mixed acid anhydride method with anacid chloride. As acid chlorides, for example, pivaloyl chloride,isobutyl chloroformate, methyl chloroformate, ethyl chloroformate,methanesulfonyl chloride and toluenesulfonyl chloride can be used. Asbases, for example, pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine and N-methylmorpholine can be used.

When this step is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, ethylacetate, acetone, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl etherand dimethoxyethane can be used, for example.

The reaction is normally carried out at a reaction temperature withinthe range of −30 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 100° C.

Step 7-B:

This step is a step for producing a cycloalkylcarbonylamino acid esterderivative represented by formula (XII) above by reacting an oxazolonederivative represented by formula (I_(o)) above with an amino acid esterderivative represented by formula (IX) above.

This step can be carried out in the presence or absence of solvent, andas solvents, for example, methylene chloride, chloroform,dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethylether, diisopropyl ether, dimethoxyethane, dimethyl sulfoxide, methanol,ethanol and 2-propanol can be used. In addition, in this step, a basecan be added as necessary. As bases, for example, pyridine,triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine andN-methylmorpholine can be used. The reaction is normally carried out ata reaction temperature within the range of −30 to 200° C. and can bepreferably allowed to proceed within the range of 20 to 200° C.

Oxazolone derivatives represented by formula (I_(o)) above include, forexample, the compounds listed below:2-phenylmethyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-phenylethyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(4-biphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(2-naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-[(RS)-2,3-tetrahydrobenzofuran-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(6-benzothiazolyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(1,3-benzoxol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(2-benzofuranyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(2-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(3-ethoxy-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(2-pyrazinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(5-methylisoxazol-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-cyclopentyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,2-(5-methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,

-   2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-methyl-2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-methyl-1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-(1H-indol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-cyclopentenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(6-hydroxy-2-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(furanyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-[(2-propoxy)carbonyl]piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-(ethoxycarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-(2-furanylcarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[(2-furanylcarbonyl)amino]methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[(benzoylamino)methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[[4-[(1-propyl)piperazin-1-yl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-furyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cyclohexyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-propyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-acetyl-piperidin-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(2-[1,4-bipiperidin]-1′-yl-4-thiazolyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(1,1-dimethylethyl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-([1,1′-biphenyl]-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(4-pyridinyl)-4-thiazolyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-aminophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-morpholinyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(5-bromo-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(4-methyl-1-piperazinyl)carbonyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(dimethylamino)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-ethynylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4′-(dimethylamino)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-methyl-1-piperazinyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[1-(2-hydroxyethyl)-4-piperidinyl]oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[(1-methyl-4-piperidinyl)oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[methyl(1-methyl-3-pyrrolidinyl)amino][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[4-(1,1-dimethylethyl)-1-piperidinyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(1-piperazinylsulfonyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(4-fluoro-4-piperidinyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[4-(2,2,2-trifluoroethyl)-1-piperazinyl]sulfonyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[(1-methyl-3-piperidinyl)oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[1-(2-methoxyethyl)-4-piperidinyl]oxy][1,1′-biphenyl]-4-yl]]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4′-[[(2S)-1-methyl-2-pyrrolidinyl]methoxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[4-[(1,1-dimethylethyl)amino]-1-piperidinyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(5-isoxazolyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-morpholinylmethyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[3-(dimethylamino)-1-pyrrolidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-methyl-1-piperazinylmethyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(1,4-dimethyl-4-piperidinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(1-methyl-4-piperidinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[(3R)-3-amino-1-pyrrolidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-piperidinyloxy)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-[2-(4-morpholinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-[(1-methylethyl)amino]-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[methyl(4-methyl-1-piperazinyl)amino]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-[methyl(1-methylethyl)amino]-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(tetrahydro-2H-pyran-4-yl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(2-methoxyethyl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(4-morpholinyl)-1-propynyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cycloheptyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cyclopropyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(diethylamino)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-methyl-4-piperazinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(1-piperazinyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-methylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(methoxymethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-chlorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-cyanophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-(phenoxymethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-chlorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-thienylmethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-methylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-hydroxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-methyl-1,2,3-thiadiazol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    and 2-(2,5-dimethyl-3-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one.

In addition, amino acid ester derivatives represented by formula (IX)above include, for example, the compounds listed below:

alanine methyl ester, N^(ω)-p-toluenesulfonyl-arginine ethyl ester,asparagine t-butyl ester, aspartic acid α-benzyl ester, aspartic aciddimethyl ester, isoasparagine ethyl ester, γ-carboxyglutamic aciddibenzyl ester, cysteine ethyl ester, S-benzyl cysteine methyl ester,cystine dimethyl ester, glutamine ethyl ester, glutamic acid di-t-butylester, histidine methyl ester, homoarginine ethyl ester, homocysteinemethyl ester, homocystine diethyl ester, homoserine benzyl ester,homophenyl alanine methyl ester, isoleucine t-butyl ester, leucinecyclohexyl ester, N^(ε)-carbobenzoxy-lysine methyl ester, methionineethyl ester, norleucine isopropyl ester, t-leucine butyl ester,norvaline methyl ester, N^(δ)-carbobenzoxy-ornithine benzyl ester,phenylalanine t-butyl ester, phenylglycine 3-pentyl ester, serine ethylester, threonine benzyl ester, tryptophan methyl ester, tyrosine ethylester, valine cyclopentyl ester, 3,4-dihydroxyphenylalanine ethyl ester,allylglycine methyl ester, neopentyl glycine t-butyl ester,allothreonine benzyl ester, homolysine methyl ester, naphthyl alanineethyl ester, α-aminoadipic acid t-butyl ester, thienyl glycine methylester, pyridylalanine benzyl ester, and cyclohexylalanine t-butyl ester.

Step 8:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by carrying out a reductionreaction after activating a cycloalkylcarbonylamino acid represented byformula (X) above by a mixed acid anhydride method.

As acid chlorides employable in the reaction for forming a mixed acidanhydride in this step, for example, pivaloyl chloride, isobutylchloroformate, methyl chloroformate, ethyl chloroformate,methanesulfonyl chloride and toluenesulfonyl chloride can be used. Asbases, for example, pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine and N-methylmorpholine can be used.

When this reaction is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, benzene,toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran,dioxane, diethyl ether, diisopropyl ether and dimethoxyethane can beused.

The reaction is normally carried out at a reaction temperature withinthe range of −50 to 200° C. and can be preferably allowed to proceedwithin the range of −20 to 50° C.

In addition, as reducing agents employable in this step, sodiumborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, andsodium dihydro-bis(2-methoxyethoxy)aluminate (Red-Al) can be used.

When this step is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, benzene,toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran,dioxane, diethyl ether, diisopropyl ether, dimethoxyethane, ethanol,2-propanol or water, etc., can be used. The reaction is normally carriedout at a reaction temperature within the range of −30 to 200° C. and canbe preferably allowed to proceed within the range of −20 to 80° C.

Cycloalkylcarbonylamino acids represented by formula (X) above include,for example, the compounds listed below:

-   N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valine,    N-[[1-[[(phenylmethoxy)    carbonyl]amino]cyclohexyl]carbonyl]-L-norleucine,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucine,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylalanine,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-tryptophan,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-tyrosine,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-histidine,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-pyridylglycine,    N-[[1-(acetamide)cyclohexyl]carbonyl]-L-valine,    N-[[1-[[(phenylmethylthio)carbonyl]amino]cyclohexyl]carbonyl]-L-valine,    N-[[1-[(1-oxo-3-phenyl-2-propenyl)amino]cyclohexyl]carbonyl]-L-valine,    N-[[1-[(1-oxo-3-phenyl-2-propynyl)amino]cyclohexyl]carbonyl]-L-valine,    and    N-[[1-[(1-oxo-3-phenyl-2-propynyl)amino]cyclohexyl]carbonyl]-L-allylglycine.

Step 9:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by reducing acycloalkylcarbonylamino acid ester derivative represented by formula(XII) above.

As reducing agents employable in this step, for example, sodiumborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, andRed-Al can be used.

When this reaction is carried out, it is preferably carried out in asolvent, and methylene chloride, chloroform, dichloroethane, benzene,toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran,dioxane, diethyl ether, diisopropyl ether and dimethoxyethane can beused, for example.

The reaction is normally carried out at a reaction temperature withinthe range of −100 to 200° C. and can be preferably allowed to proceedwithin the range of −80 to 100° C.

Cycloalkylcarbonylamino acid ester derivatives represented by formula(XII) above include, for example, the compounds listed below:

-   N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valine    methyl ester,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucine    ethyl ester,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine benzyl    ester,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucine    t-butyl ester,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine    ethyl ester,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylalanine    benzyl ester,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-tryptophan    methyl ester,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-tyrosine    propyl ester,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine    2-propyl ester,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-hystidine    butyl ester,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-pyridyl    glycine t-butyl ester,    N-[[1-(acetamido)cyclohexyl]carbonyl]-L-valine methyl ester,    N-[[1-[[(phenylmethylthio)carbonyl]amino]cyclohexyl]carbonyl]-L-valine    benzyl ester,    N-[[1-[(1-oxo-3-phenyl-2-propenyl)amino]cyclohexyl]carbonyl]-L-valine    ethyl ester,    N-[[1-[(1-oxo-3-phenyl-2-propynyl)amino]cyclohexyl]carbonyl]-L-valine    benzyl ester, and    N-[[1-[(1-oxo-3-phenyl-2-propynyl)amino]cyclohexyl]carbonyl]-L-allylglycine    t-butyl ester.

Step 10:

This step is a step for producing a cycloalkylcarbonylamino aldehydederivative represented by formula (XIII) above by oxidizing acycloalkylcarbonylamino alcohol derivative represented by formula (XI)above.

In the oxidation reaction employable in this step, activated DMSO(dimethyl sulfoxide) oxidation can be used. Electrophilic activatingreagents used here include, for example, dicyclohexylcarbodiimide,phosphorous pentoxide, pyridine-sulfur trioxide complex, aceticanhydride, mercury (II) acetate and oxalyl chloride. A hydrogen donorsuch as phosphoric acid, trifluoroacetic acid, dichloroacetic acid,pyridine-phosphoric acid or pyridine-trifluoroacetic acid can also beadded in this step as necessary. In addition, an amine such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine can alsobe added as necessary.

This step can be carried out in dimethyl sulfoxide, and a solvent suchas methylene chloride, chloroform, dichloroethane, toluene, acetone ortetrahydrofuran can also be added as necessary.

The reaction is normally carried out at a reaction temperature withinthe range of −80 to 200° C. and can be preferably allowed to proceedwithin the range of −40 to 40° C.

In addition, in this step, an oxidation reaction can also be carried outby preparing an active species having a structure resembling anactivated DMSO reaction from a sulfide and halogen.

As sulfides employable in this step, dimethyl sulfide or methyl phenylsulfide can be used, for example. As halogenating agents,N-chlorosuccinimide, chlorine, etc. can be used.

In this step, an amine such as triethylamine, N,N-diisopropylethylamine,N-methylmorpholine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can alsobe added as necessary.

This step is preferably carried out in a solvent, and as solvents,methylene chloride, chloroform, dichloroethane, toluene;tetrahydrofuran, etc. can be used.

The reaction is normally carried out at a reaction temperature withinthe range of −80 to 200° C. and can be preferably allowed to proceedwithin the range of −40 to 40° C.

In addition, oxidation can also be carried out in this step using ahypervalent iodine compound reagent. As hypervalent iodine compoundsemployable in this step, Dess-Martin reagent(1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one), IBX(1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide), etc. can be used.

A base such as pyridine or sodium hydrogencarbonate can be added in thisstep as necessary.

This step is preferably carried out in a solvent, and as solvents, forexample, methylene chloride, chloroform, dichloroethane, benzene,toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran,dioxane and dimethoxyethane can be used.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

In addition, this step can also be carried out using oxidation(oppenauer's oxidation) with aluminum alkoxide and a hydrogen acceptor.As aluminum alkoxides, aluminum isopropoxide and aluminum t-butoxide canbe used, for example.

As hydrogen acceptors, for example, benzoquinone, benzophenone, acetone,cyclohexanone and benzaldehyde can be used.

This step is preferably carried out in a solvent, and as solvents, forexample, benzene, toluene and xylene can be used.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 150° C.

In addition, this step can also be carried out using an oxidationreaction with tetrapropylammonium perruthenate(TPAP).N-methylmorpholine-N-oxide or molecular oxygen can be used for theoxidizing agent.

This step is preferably carried out in a solvent, and as solvents, forexample, methylene chloride, acetonitrile and toluene can be used.

A type 4A molecular sieve can be added in this step as necessary.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

In addition, this step can also use an oxidation reaction with2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or derivativethereof.

As the oxidizing agent, hypochlorous acid salt is preferable, andbromous acid salt, N-chlorosuccinimide, etc. can be used.

This step is preferably carried out in a solvent, and as solvents, forexample, dimethyl sulfoxide, N,N-dimethylformamide, methylene chloride,acetonitrile, toluene and ethyl acetate can be used.

In addition, sodium bromide or water can also be added in this step asnecessary.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

Specific examples of an alcohol derivative (XI), in which B is ahydroxymethyl group, and an aldehyde derivative (XIII), in which B is aformyl group, in the cycloalkane carboxamide derivatives represented bygeneral formula (I) above of the present invention include the compoundslisted below.N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinol,N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinol,N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinol,N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninol,N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol,N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol,N-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol,N-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino)cyclohexyl]carbonyl]-L-phenylglycinol,N-[[1-[[[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol,N-[[1-[[[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol,N-[[1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[(3-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol,N-[[1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol,

-   N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal,    N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinal,    N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal,    N-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinal,    N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinal,    N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninal,    N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal,    N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal,    N-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolylphenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal,    N-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal,    N-[[1-[[[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal,    N-[[1-[[[2-[4-(4-morpholinyl)-1-piperazinyl]-4    thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal,    N-[[1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal,    N-[[1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinal,    N-[[1-[(3-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal, and    N-[[1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal.

The effective amount of these compounds or pharmaceutically acceptablesalts thereof as pharmaceuticals in the case of administering to humansvaries depending on such factors as the degree of the effective activitythereof, patient age and symptoms of the target disease, and theeffective amount is normally 0.001 to 100 mg and preferably 0.01 to 50mg per kilogram of human body weight per day. In addition, in the caseof administering these compounds for the purpose of treatment, thesecompounds or pharmaceutically acceptable salts thereof are used in theform of a pharmaceutical composition containing one of these compoundsor a salt thereof as an active ingredient in combination with apharmaceutically allowable carrier, examples of which include an organicor inorganic solid or liquid excipient, etc. suitable for not only oraladministration but also parenteral administration, external use orinhalation. Examples of the forms of these pharmaceutical compositionsinclude capsules, tablets, sugar-coated tablets, granules, liquids,suspensions and emulsions. An adjuvant, stabilizer, lubricant,emulsifier, buffer or other commonly used additive can be added to thesepreparations as necessary.

A cycloalkane carboxamide derivative represented by formula (I) of thepresent invention has highly active and highly selective inhibitoryactivity against cathepsin K as is clear from the test examples to bedescribed later, as a result of having this selective inhibitoryactivity against cathepsin K, and thus, it is expected to be used as auseful drug for prevention or treatment of osteoporosis, hypercalcemia,osteoarthrosis and rheumatoid arthritis.

The present invention is explained below in further detail by way ofreference examples and examples, but the present invention is notlimited to these examples provided they do not exceed the gist thereof.

Furthermore, “%” refers to “1% by weight” unless specifically indicatedotherwise.

In addition, synthesis examples of the cycloalkylcarboxylic acidrepresented by formula (VI) above and esters thereof, as well assynthesis examples of the oxazolone derivative represented by formula(I_(o)), which are intermediates for producing the cycloalkanecarboxamide derivatives of the present invention, are indicated asreference examples.

REFERENCE EXAMPLE 1 1-[(Phenylacetyl)amino]cyclohexanecarboxylic acidphenylmethyl ester

1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 mlof tetrahydrofuran, and 1.55 g (10 mmol) of phenylacetyl chloride wasadded dropwise thereto under ice-cooling, followed by stirring of themixture overnight. The reaction mixture was concentrated under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogen sulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine, followed by drying with anhydrous sodium sulfate. Afterthe solvent was distilled off under reduced pressure, the residue waspurified by silica gel chromatography to obtain 3.21 g (91%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.10-1.23 (3H, m), 1.50-1.58 (3H, m), 1.74-1.80 (2H,m), 1.95-1.98 (2H, m), 3.57 (2H, s), 5.12 (2H, s), 5.48 (1H, br-s),7.24-7.38 (10H, m)

REFERENCE EXAMPLE 2 1-[(Phenylacetyl)amino]cyclohexanecarboxylic acid

2.69 g (9.1 mmol) of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acidphenylmethyl ester obtained in Reference example 1 was dissolved in 100ml of methanol, and 300 mg of 10% palladium-carbon was added thereto,followed by stirring of the mixture at room temperature under a hydrogenatmosphere overnight. After the reaction solution was filtered, thefiltrate was concentrated under reduced pressure to obtain 1.96 g (98%)of the title compound.

1H-NMR (CDCl₃, δ): 1.01-1.10 (2H, m), 1.18-1.26 (1H, m), 1.49-1.59 (3H,m), 1.75-1.82 (2H, m), 1.97-2.00 (2H, m), 3.66 (2H, s), 5.67 (1H, br-s),7.29-7.34 (3H, m), 7.37-7.40 (2H, m)

REFERENCE EXAMPLE 3 1-[(1-Oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.68 g (10 mmol) of 3-phenylpropionyl chloride was used instead ofphenylacetyl chloride in the process according to Reference example 1 toobtain 3.47 g (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.19-1.26 (3H, m), 1.50-1.61 (3H, m), 1.78-1.84 (2H,m), 1.96-2.05 (2H, m), 2.50 (2H, t, J=7 Hz), 2.93 (2H, t, J=7 Hz), 5.13(2H, s), 5.45 (1H, br-s), 7.18-7.21 (4H, m), 7.26-7.37 (6H, m)

REFERENCE EXAMPLE 4 1-[(1-Oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid

3.47 g (9.5 mmol) of1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid phenylmethyl ester in the process according to Reference example 2to obtain 2.35 g (90%) of the title compound.

1H-NMR (CDCl₃, δ): 1.16-1.25 (3H, m), 1.48-1.51 (1H, m), 1.52-1.62 (2H,m), 1.84-1.97 (4H, m), 2.62 (2H, t, J=7 Hz), 3.00 (2H, t, J=7 Hz), 5.43(1H, br-s), 7.21-7.26 (3H, m), 7.29-7.33 (2H, m)

REFERENCE EXAMPLE 5 1-(Benzoylamino)cyclohexanecarboxylic acidphenylmethyl ester

1.41 g (10 mmol) of benzoyl chloride was used instead of phenylacetylchloride in the process according to Reference example 1 to obtain 3.39g (quantitative) of the title compound.

1H-NMR (CDC₃, δ): 1.33-1.40 (1H, m), 1.45-1.54 (2H, m), 1.62-1.76 (3H,m), 1.93-1.99 (2H, m), 2.19-2.22 (2H, m), 5.17 (2H, s), 6.25 (1H, br-s),7.25-7.32 (4H, m), 7.41-7.45 (3H, m), 7.49-7.52 (1H, m), 7.75-7.77 (2H,m)

REFERENCE EXAMPLE 6 1-(Benzoylamino)cyclohexanecarboxylic acid

3.39 g (10 mmol) of 1-(benzoylamino)cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 2.44 g (99%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.38-1.55 (3H, m), 1.67-1.71 (1H, m), 1.75-1.79 (2H,m), 1.98-2.04 (2H, m), 2.24-2.27 (2H, m), 6.26 (1H, br-s), 7.46 (1H, td,J=7 Hz, 1 Hz), 7.48 (1H, td, J=7 Hz, 1 Hz), 7.57 (1H, td, 7 Hz, 1 Hz),7.79-7.82 (2H, m)

REFERENCE EXAMPLE 7 1-[(4-Biphenylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

2.11 g (11 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 2.33 g (10 mmol) of1-aminocyclohexanecarboxylic acid phenylmethyl ester, 1.68 g (11 mmol)of 1-hydroxybenzotriazole and 3.23 g (10 mmol) of 4-biphenylcarboxylicacid in 120 ml of methylene chloride under ice-cooling. After themixture was stirred at room temperature overnight, the reaction solutionwas concentrated under reduced pressure, ethyl acetate was addedthereto, and the mixture was successively washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel chromatographyto obtain 3.51 g (85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.38-1.41 (1H, m), 1.51-1.61 (2H, m), 1.66-1.80 (3H,m), 1.95-2.05 (2H, m), 2.23-2.31 (2H, m), 5.20 (2H, s), 6.38 (1H, br-s),7.24-7.34 (7H, m), 7.55-7.60 (2H, m), 7.81 (1H, dd, J=8 Hz, 1 Hz),7.87-7.91 (3H, m), 8.26 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 8 1-[(4-Biphenylcarbonyl)amino]cyclohexanecarboxylicacid

3.51 g (8.5 mmol) of 1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 2.75 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.48 (1H, m), 1.48-1.60 (2H, m), 1.66-1.73 (1H,m), 1.73-1.82 (2H, m), 2.00-2.10 (2H, m), 2.27-2.35 (2H, m), 6.32 (1H,br-s), 7.39-7.43 (1H, m), 7.46-7.49 (2H, m), 7.61-7.66 (2H, m),7.68-7.70 (2H, m), 7.87-7.89 (2H, m)

REFERENCE EXAMPLE 9 1-[(2-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.28 g (7.4 mmol) of 2-naphthoeic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference example7 to obtain 2.12 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.48-1.61 (2H, m), 1.64-1.78 (3H,m), 1.95-2.01 (2H, m), 2.21-2.24 (2H, m), 5.19 (2H, s), 6.27 (1H, br-s),7.27-7.36 (3H, m), 7.40 (1H, td, J=7 Hz, 1 Hz), 7.46-7.49 (2H, m),7.61-7.63 (2H, m), 7.65-7.67 (2H, m), 7.83-7.85 (2H, m)

REFERENCE EXAMPLE 10 1-[(2-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid

2.12 g (5.5 mmol) of 1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 1.63 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.41-1.45 (1H, m), 1.52-1.60 (2H, m), 1.70-1.74 (1H,m), 1.77-1.82 (2H, m), 2.03-2.09 (2H, m), 2.29-2.32 (2H, m), 6.41 (1H,br-s), 7.56-7.63 (2H, m), 7.83 (1H, dd, J=8 Hz, 2 Hz), 7.89-7.96 (3H,m), 8.33 (1H, s)

REFERENCE EXAMPLE 11 1-[(1-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.72 g (10 mmol) of 1-naphthoeic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference example7 to obtain 3.87 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.42 (1H, m), 1.45-1.60 (2H, m), 1.65-1.71 (1H,m), 1.71-1.80 (2H, m), 1.98-2.05 (2H, m), 2.24-2.32 (2H, m), 5.26 (2H,s), 6.10 (1H, br-s), 7.32-7.37 (3H, m), 7.40-7.45 (4H, m), 7.48-7.52(1H, m), 7.57 (1H, dd, J=7 Hz, 1 Hz), 7.85 (1H, dd, J=7 Hz, 1 Hz), 7.91(1H, dd, J=7 Hz, 1 Hz), 8.25 (1H, dd, J=7 Hz, 1 Hz)

REFERENCE EXAMPLE 121-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

12.22 g (75.4 mmol) of benzofuran-2-carboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference example7 to obtain 21.3 g (75%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26-1.42 (1H, m), 1.50-1.61 (2H, m), 1.64-1.77 (3H,m), 1.95-2.04 (2H, m), 2.21-2.28 (2H, m), 5.19 (2H, s), 6.77 (1H, br-s),7.25-7.34 (6H, m), 7.44 (1H, td, J=8 Hz, 2 Hz), 7.52 (1H, dd, J=8 Hz, 2Hz), 7.57 (1H, dd, J=8 Hz, 2 Hz), 7.68 (1H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 131-[[[(RS)-2,3-Tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylicacid

1.5 g of 10% palladium-carbon was added to a solution of 15 g (40 mmol)of 1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester in 300 ml of 2-propanol, and the mixture was stirredat 60° C. under a hydrogen atmosphere for 20 hours. After the reactionsolution was filtered, the filtrate was concentrated under reducedpressure to obtain 11.57 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.07-1.19 (1H, m), 1.21-1.36 (2H, m), 1.50-1.63 (2H,m); 1.65-1.71 (1H, m), 1.80-1.88 (1H, m), 1.89-1.95 (1H, m), 2.04-2.15(2H, m), 3.42 (1H, dd, J=17 Hz, 7 Hz), 3.60 (1H, dd, J=17 Hz, 7 Hz),5.18 (1H, dd, J=7 Hz, 7 Hz), 6.84 (1H, br-s), 6.91 (1H, d, J=8 Hz), 6.96(1H, dd, J=8 Hz, 1 Hz), 7.18 (1H, td, J=8 Hz, 1 Hz), 7.22 (1H, dd, J=8Hz, 1 Hz)

REFERENCE EXAMPLE 14 1-[(2-Furanylcarbonyl)amino]cyclohexanecarboxylicacid

71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to 250ml of an aqueous solution of 20 g (0.5 mol) of sodium hydroxide, and themixture was stirred at 80° C. for 2 hours. The mixed solution was cooledwith ice-water, and 71.8 g (0.2 mol) of 2-furancarbonyl chloride and 100ml of an aqueous solution of 24 g (0.6 mol) of sodium hydroxide weresimultaneously added thereto over approximately 1 hour. The temperatureof the reaction solution was slowly returned to room temperature and thesolution was stirred overnight. After 80 ml of ethyl acetate was addedto the reaction solution and the solution was stirred for 1 hour, theinsolubles were removed by filtration. The aqueous layer was separatelycollected and 49 ml of concentrated hydrochloric acid was added theretounder ice-cooling. The precipitated crystal was collected by filtrationand dried under reduced pressure to obtain 112.6 g (95%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.35-1.41 (1H, m), 1.48-1.53 (2H, m), 1.64-1.67 (1H,m), 1.71-1.76 (2H, m), 1.96-2.02 (2H, m), 2.20-2.24 (2H, m), 6.48 (1H,br-s), 6.55 (1H, dd, J=4 Hz, 2 Hz), 7.19 (1H, dd, J=4 Hz, 1 Hz), 7.50(1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 15 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 98.8 g (500 mmol) of1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g(550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 mlof methylene chloride under ice-cooling. After the mixture was stirredat room temperature overnight, the reaction solution was concentratedunder reduced pressure. Ethyl acetate was added to the residue and themixture was successively washed with water, a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with anhydrous sodiumsulfate. After the solvent was distilled off under reduced pressure, theobtained crystal was washed with diisopropyl ether to give 114 g (91%)of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m), 1.62-1.73 (3H,m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s),6.23 (1H, dd, J=2 Hz, 1 Hz), 7.44 (1H, dd, J=2 Hz, 1 Hz), 7.94 (1H, dd,J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 16 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylicacid

450 ml of 2N aqueous sodium hydroxide solution was added to a solutionof 75.4 g (300 mmol) of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester in450 ml of tetrahydrofuran, and the mixture was refluxed under heatingfor 3 hours. After ether was added to the reaction solution to wash, theaqueous layer was neutralized by concentrated hydrochloric acid andextracted with ethyl acetate. After the obtained organic layer waswashed with saturated brine and it was dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtain68.8 g (97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.50 (3H, m), 1.58-1.64 (1H, m), 1.68-1.80° (2H,m), 1.98-2.05 (2H, m), 2.14-2.23 (2H, m), 5.87 (1H, s), 6.63 (1H, d, J=2Hz), 7.49 (1H, d, J=2 Hz), 8.00 (1H, s)

REFERENCE EXAMPLE 171-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidmethyl ester

80 g (362 mmol) of 2-furanacrylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 89 g (89%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.39 (1H, m), 1.40-1.51 (2H, m), 1.58-1.71 (3H,m), 1.88-1.95 (2H, m), 2.05-2.14 (2H, m), 3.73 (3H, s), 5.67 (1H, br-s),6.35 (1H, d, J=16 Hz), 6.45 (1H, dd, J=3 Hz, 2 Hz), 6.54 (1H, d, J=3Hz), 7.37 (1H, d, J=16 Hz), 7.40 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 181-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acid

44.9 g (162 mmol) of1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 37.5 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.85 (6H, m), 1.96-2.05 (2H, m), 2.15-2.18 (2H,m), 5.66 (1H, br-s), 6.36 (1H, d, J=15 Hz), 6.49 (1H, dd, J=3 Hz, 2 Hz),6.64 (1H, d, J=3 Hz), 7.48 (1H, d, J=15 Hz), 7.49 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 191-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

3.11 g (15 mmol) of 1-aminocyclohexanecarboxylic acid ethyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidmethyl ester hydrochloride and 2.43 g (15 mmol) ofbenzofuran-2-carboxylic acid was used instead of 3-furancarboxylic acidin the process according to Reference example 15 to obtain 3.80 g (80%)of the title compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.33-1.42 (1H, m) 1.50-1.62(2H, m), 1.65-1.78 (3H, m), 1.94-2.02 (2H, m), 2.19-227 (2H, m), 4.21(2H, q, J=7 Hz), 6.75 (1H, br-s), 7.30 (1H, td, J=8 Hz, 1 Hz), 7.43 (1H,td, J=8 Hz, 1 Hz), 7.45 (1H, d, J=1 Hz), 7.53 (1H, dd, J=8 Hz, 1 Hz),7.67 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 201-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid

3.80 g (12 mmol) of1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid ethyl esterwas used instead of 1-[(3-furanylcarbonyl)amino)cyclohexanecarboxylicacid methyl ester in the process according to Reference example 16 toobtain 3.42 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.44 (1H, m), 1.50-1.62 (2H, m), 1.65-1.73 (1H,m), 1.74-1.82 (2H, m), 2.00-2.08 (2H, m), 2.25-2.33 (2H, m), 6.77 (1H,br-s), 7.32 (1H, td, J=8 Hz, 1 Hz), 7.46 (1H, td, J=8 Hz, 1 Hz), 7.53(1H, d, J=1 Hz), 7.55 (1H, dd, J=8 Hz, 1 Hz), 7.70 (1H, dd, J=8 Hz, 1Hz)

REFERENCE EXAMPLE 21 1-[(Cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

3.85 g (30 mmol) of cyclohexanecarboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference example7 to obtain 4.77 g (46%) of the title compound.

1H-NMR (CDCl₃, δ): 1.17-1.45 (8H, m), 1.59-1.77 (4H, m), 1.73-1.88 (6H,m), 2.03-2.11 (3H, m), 5.12 (2H, s), 5.55 (1H, br-s), 7.23-7.36 (5H, m)

REFERENCE EXAMPLE 22 1-[(Cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid

5.62 g (16.3 mmol) of 1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 4.15 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.18-1.50 (8H, m), 1.60-1.76 (4H, m), 1.78-1.95 (6H,m), 2.06-2.14 (2H, m), 2.16-2.23 (1H, m), 5.58 (1H, br-s)

REFERENCE EXAMPLE 231-[(6-Benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester

1.15 g (6.4 mmol) of benzothiazole-6-carboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference example7 to obtain 1.58 g (62%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.43 (1H, m), 1.49-1.60 (2H, m), 1.61-1.78 (3H,m), 1.96-2.06 (2H, m), 2.20-2.27 (2H, m), 5.19 (2H, s), 6.30 (1H, br-s),7.28-7.75 (5H, m), 7.86 (1H, dd, J=7 Hz, 2 Hz), 8.17 (1H, dd, J=7 Hz, 1Hz), 8.41 (1H, dd, J=2 Hz, 1 Hz), 9.12 (1H, s)

REFERENCE EXAMPLE 241-[(6-Benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid

1.18 g (30 mmol) of1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 0.77 g (84%) ofthe title compound.

1H-NMR (CD₃OD, δ): 1.38-1.46 (1H, m), 1.60-1.76 (5H, m), 1.91-2.01 (2H,m), 2.21-2.28 (2H, m), 7.98 (1H, dd, J=7 Hz, 2 Hz), 8.12 (1H, dd, J=7Hz, 1 Hz), 8.54 (1H, dd, J=2 Hz, 1 Hz), 9.37 (1H, s)

REFERENCE EXAMPLE 251-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

139 mg (1.0 mmol) of 6-hydroxy-3-pyridinecarboxylic acid was usedinstead of 4-biphenylcarboxylic acid in the process according toReference example 7 to obtain 222 mg (62%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.40 (1H, m), 1.42-1.54 (2H, m), 1.62-1.73 (3H,m), 1.91-1.98 (2H, m), 2.13-2.20 (2H, m), 5.17 (2H, s), 6.22 (1H, s),6.54 (1H, d, J=10 Hz), 7.26-7.35 (5H, m), 7.76 (1H, dd, J=10 Hz, 3 Hz),7.93 (1H, d, J=3 Hz)

REFERENCE EXAMPLE 261-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

760 mg (2.2 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 565 mg(quantitative) of the title compound.

1H-NMR (CD₃OD, δ): 1.21-1.30 (1H, m), 1.43-1.54 (5H, m), 1.67-1.74 (2H,m), 2.03-2.09 (2H, m), 6.33 (1H, d, J=9 Hz), 7.84 (1H, dd, J=9 Hz, 3Hz), 8.05 (1H, d, J=3 Hz)

REFERENCE EXAMPLE 27 1-[(2-Thienylcarbonyl)amino]cyclohexanecarboxylicacid

100 g (680 mmol) of 2-thiophenecarbonyl chloride was used instead of2-furancarbonyl chloride in the process according to Reference example14 to obtain 57.6 g (51) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.54 (3H, m), 1.65-1.80 (3H, m), 1.98-2.05 (2H,m), 2.21-2.27 (2H, m), 6.06 (1H, br-s), 7.13 (1H, dd, J=5 Hz, 3 Hz),7.57 (1H, dd, J=5 Hz, 1 Hz), 7.59 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 28 1-[(2-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of 2-pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 600 mg (76%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.42 (1H, m), 1.51-1.73 (5H, m), 1.95 (2H, td,J=13 Hz, 4 Hz), 1.99-2.08 (2H, m), 3.73 (3H, s), 7.44 (1H, ddd, J=8 Hz,5 Hz, 2 Hz), 7.84 (1H, dd, J=8 Hz, 2 Hz), 8.16 (1H, d, J=8 Hz), 8.33(1H, s), 8.57 (1H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 29 1-[(2-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

539 mg (2 mmol) of 1-[(2-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 479 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.48-1.57 (2H, m), 1.62-1.78 (3H,m), 1.98 (2H, m), 2.25-2.35 (2H, m), 7.50 (1H, ddd, J=8 Hz, 5 Hz, 2 Hz),7.89 (1H, dd, J=8 Hz, 2 Hz), 8.19 (1H, d, J=8 Hz), 8.59 (1H, s), 8.60(1H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 30 1-[(3-Thienylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

384 mg (3 mmol) of 3-thiophenecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 759 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.42-1.55 (2H, m), 1.61-1.75 (3H,m), 1.90-1.99 (2H, m), 2.11-2.18 (2H, m), 3.74 (3H, s), 6.26 (1H, br-s),7.35 (1H, dd, J=5 Hz, 2 Hz), 7.39 (1H, dd, J=5 Hz, 2 Hz), 7.88 (1H, dd,J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 31 1-[(3-Thienylcarbonyl)amino]cyclohexanecarboxylicacid

759 mg (2.8 mmol) of 1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 692 mg (96%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.24-1.32 (1H, m), 1.45-1.55 (5H, m) 1.72-1.78 (2H,m), 2.05-2.12 (2H, m), 7.50 (1H, dd, J=5 Hz, 2 Hz), 7.57 (1H, dd, J=5Hz, 2 Hz), 7.96 (1H, br-s), 8.21 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 321-[[(3-Ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 581 mg (3 mmol) of1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 482 mg(3.1 mmol) of 1-hydroxybenzotriazole, 517 mg (3 mmol) of3-ethoxy-2-thiophenecarboxylic acid and 1.16 g (9 mmol) ofdiisopropylethylamine in 10 ml of methylene chloride under ice-cooling.After the solution was stirred at room temperature overnight, thereaction solution was concentrated under reduced pressure, ethyl acetatewas added thereto, and the mixture was washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and then saturated brine, followed by dryingwith anhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diisopropyl ether was added to the residue, followedby stirring overnight and the crystal was collected by filtration.Subsequently, the obtained crystal was dissolved in 3 ml oftetrahydrofuran solution, 2.8 ml of 2N—NaOH aqueous solution was addedthereto, and the mixture was refluxed under heating for 3 hours. Etherwas added to the reaction solution and the aqueous layer was separated.After the separated aqueous layer was neutralized by concentratedhydrochloric acid, the layer was extracted with ethyl acetate. After theobtained organic layer was washed with saturated brine, it was driedwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 656 mg (73%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.40 (1H, m), 1.43-1.54 (2H, m), 1.50 (3H, t,J=7 Hz), 1.62-1.76 (3H, m), 1.90-2.00 (2H, m), 2.22-2.30 (2H, m), 4.30(2H, q, J=7 Hz), 6.87 (1H, d, J=6 Hz), 7.49 (1H, d, J=6 Hz), 7.60 (1H,s)

REFERENCE EXAMPLE 331-[[(S)-1-Oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid methylester

451 mg (3 mmol) of (S)-(+)-2-phenylpropionic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 601 mg (69%) of the title compound.

1H-NMR (CDCl₃, δ): 1.06-1.22 (2H, m), 1.48-1.61 (7H, m), 1.71-1.77 (2H,m), 1.90-1.96 (2H, m), 3.60 (1H, q, 7 Hz), 3.67 (3H, s), 5.40 (1H,br-s), 7.27-7.39 (5H, m)

REFERENCE EXAMPLE 341-[[(S)-1-Oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid

608 mg (2.1 mmol) of1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 366 mg (63%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.08-1.21 (2H, m), 1.28-1.47 (7H, m) 1.53-1.62 (2H,m), 1.93 (2H, br-s), 3.79 (1H, q, J=7 Hz), 7.18-7.21 (1H, m), 7.27-7.33(4H, m), 7.90 (1H, s), 12.00 (1H, s)

REFERENCE EXAMPLE 35 1-[(2-Pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

372 mg (3 mmol) of 2-pyrazinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 476 mg (60%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.40 (1H, m), 1.47-1.59 (2H, m), 1.65-1.75 (3H,m), 1.94-2.00 (2H, m), 2.18-2.29 (2H, m), 3.75 (3H, s), 8.03 (1H, s),8.55 (1H, dd, J=3 Hz, 1 Hz), 8.77 (1H, d, J=3 Hz), 9.38 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 36 1-[(2-Pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid

476 mg (1.8 mmol) of 1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 356 mg (79%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.28-1.59 (6H, m), 1.79 (2H, td, J=12 Hz, 4 Hz),2.10-2.19 (2H, m), 8.35 (1H, s), 8.75 (1H, d, J=2 Hz), 8.89 (1H, d, J=2Hz), 9.14 (1H, d, J=2 Hz), 12.42 (1H, s)

REFERENCE EXAMPLE 371-[[(5-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

427 mg (3 mmol) of 5-methyl-2-thiophenecarboxylic acid was used insteadof 3-furancarboxylic acid in the process according to Reference example15 to obtain 812 mg (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.72 (6H, m), 1.92 (2H, td, J=13 Hz, 4 Hz),2.11-2.19 (2H, m), 2.51 (3H, s), 3.73 (3H, s), 5.95 (1H, s), 6.74 (1H,d, J=4 Hz), 7.34 (1H, d, J=4 Hz)

REFERENCE EXAMPLE 381-[[(5-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

812 mg (2.9 mmol) of1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 771 mg (99%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.21-1.38 (1H, m), 1.52 (5H, br-s), 1.68-1.80 (2H,m), 2.01-2.12 (2H, m), 2.46 (3H, s), 6.84 (1H, d, J=4 Hz), 7.70 (1H, s),8.02 (1H, s)

REFERENCE EXAMPLE 391-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 512 mg (3 mmol) of 4-methoxybenzoyl chloride wasused instead of phenylacetyl chloride in the process according toReference example 1 to obtain 619 mg (71%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.49-1.74 (5H, m), 1.94 (2H, td,J=13 Hz, 4 Hz), 2.12-2.22 (2H, m), 3.73 (3H, s), 3.85 (3H, s), 6.16 (1H,br-s), 6.92 (2H, dd, J=7 Hz, 2 Hz), 7.76 (2H, dd, J=7 Hz, 2 Hz)

REFERENCE EXAMPLE 401-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid

619 mg (2.1 mmol) of1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 552 mg (94%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.38 (1H, m), 1.51-1.60 (5H, br-s), 1.65-1.79(2H, m), 2.04-2.19 (2H, m), 3.81 (3H, s), 6.98 (2H, d, J=9 Hz), 7.83(2H, d, J=9 Hz), 8.04 (1H, s), 12.3 (1H, br-s)

REFERENCE EXAMPLE 411-[[(3-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 482 mg (3 mmol) of 3-methyl-2-thiophenecarbonylchloride was used instead of phenylacetyl chloride in the processaccording to Reference example 1 to obtain 394 mg (47%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.49-1.53 (2H, m), 1.70-1.72 (3H,m), 1.92 (2H, td, J=12 Hz, 4 Hz), 2.11-2.22 (2H, m), 2.36 (3H, s), 3.74(3H, s), 6.33 (1H, d, J=2 Hz), 6.44 (1H, br-s), 7.30 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 421-[[(3-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

394 mg (1.4 mmol) of1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 330 mg (88%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.36-1.53 (3H, m), 1.68-1.78 (3H, m), 1.96-2.05 (2H,m), 1.99-2.08 (2H, m), 2.55 (3H, s), 5.91 (1H, s), 6.94 (1H, d, J=5 Hz),7.35 (1H, d J=5 Hz)

REFERENCE EXAMPLE 431-[[(3-Methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid

756 mg (6 mmol) of 3-methyl-2-furancarboxylic acid was used instead of3-ethoxy-2-thiophenecarboxylic acid in the process according toReference example 32 to obtain 902 mg (59%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.20-1.38 (1H, m), 1.40-1.59 (5H, m) 1.70-1.80 (2H,m), 2.02-2.18 (2H, m), 2.25 (3H, s), 6.50 (1H, d, J=1 Hz), 7.67 (1H, s),7.68 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 44 1-[(3-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of 3-pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 539 mg (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.45-1.55 (2H, m), 1.62-1.78 (3H,m), 1.92-2.01 (2H, m), 2.12-2.21 (2H, m), 3.75 (3H, s), 6.27 (1H, s),7.40 (1H, dd, J=8 Hz, 5 Hz), 8.12 (1H, d, J=8 Hz), 8.74 (1H, d, J=5 Hz),9.00 (1H, s)

REFERENCE EXAMPLE 45 1-[(3-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

539 mg (2 mmol) of 1-[(3-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 508 mg(quantitative) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.35 (1H, m), 1.49-1.62 (5H, m) 1.69-1.82 (2H,m), 2.09-2.17 (2H, m), 7.50 (1H, dd, J=8 Hz, 5 Hz), 8.16 (1H, d, J=8Hz), 8.44 (1H, s), 8.71 (1H, d, J=5 Hz), 8.97 (1H, s), 12.24 (1H, br-s)

REFERENCE EXAMPLE 461-[[(1-Methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

375 mg (3 mmol) of 1-methyl-2-pyrrolecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 320 mg (40%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.40 (1H, m), 1.44-1.55 (2H, m), 1.61-1.74 (3H,m), 1.86-1.95 (2H, m), 2.05-2.16 (2H, m), 3.73 (3H, s), 3.89 (3H, s),5.97 (1H, s), 6.09 (1H, dd, J=4 Hz, 3 Hz), 6.59 (1H, dd, J=4 Hz, 2 Hz),6.71 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 471-[[(1-Methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid

320 mg (1.2 mmol) of1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 187 mg (62%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.31-1.53 (3H, m), 1.62-1.79 (3H, m), 1.91-2.02 (2H,m), 2.18-2.24 (2H, m), 3.93 (3H, s), 5.92 (1H, s), 6.14 (1H, dd, J=4 Hz,3 Hz), 6.68 (1H, dd, J=4 Hz, 2 Hz), 6.81 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 481-[((R)-1-Oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid methylester

451 mg (3 mmol) of (R)-(−)-2-phenylpropionic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 435 mg (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.03-1.22 (3H, m), 1.48-1.62 (6H, m), 1.88-2.00 (2H,m), 3.60 (3H, q, J=7 Hz), 3.68 (3H, s), 5.40 (1H, br-s), 7.27-7.39 (5H,m)

REFERENCE EXAMPLE 491-[((R)-1-Oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid

435 mg (1.5 mmol) of1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 349 mg (84%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.15-1.23 (2H, m), 1.29 (3H, d, J=7 Hz), 1.35-1.53(4H, m), 1.53-1.63 (2H, m), 1.91 (2H, br-s), 3.78 (1H, q, J=7 Hz),7.18-7.20 (1H, m), 7.21-7.32 (4H, m), 7.90 (1H, s), 12.00 (1H, s)

REFERENCE EXAMPLE 501-[(1H-Indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

483 mg (3 mmol) of indole-5-carboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 766 mg (85%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.16-1.33 (1H, m), 1.54-1.63 (5H, m), 1.75-1.80(2H, m), 2.04-2.18 (2H, m), 3.33 (3H, s), 6.52-6.56 (1H, m), 7.40 (1H,s), 7.41-7.44 (1H, m), 7.60 (1H, dd, J=9 Hz, 2 Hz), 8.14 (1H, d, J=2Hz), 8.18 (1H, s), 11.32 (1H, s)

REFERENCE EXAMPLE 511-[(1H-Indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid

766 mg (2.6 mmol) of1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl esterwas used instead of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference example 16 toobtain 561 mg (77%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.38 (1H, m), 1.55-1.62 (5H, m), 1.63-1.79(2H, m), 2.10-2.22 (2H, m), 6.54 (1H, d, J=3 Hz), 7.40-7.43 (2H, m),7.60 (1H, dd, J=3 Hz, 1 Hz), 8.03 (1H, s), 8.14 (1H, s), 11.31 (1H, s),12.04 (1H, s)

REFERENCE EXAMPLE 521-[(1-Cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid methylester

366 mg (3 mmol) of 1-cyclopentenecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 717 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.44 (2H, m), 1.60-1.70 (4H, m), 1.87 (2H, td,J=9 Hz, 4 Hz), 1.99-2.09 (4H, m), 2.49 (2H, m), 2.58 (2H, m), 3.72 (3H,s), 5.75 (1H, br-s), 6.55 (1H, t, J=2 Hz)

REFERENCE EXAMPLE 531-[(1-Cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid

717 mg (2.9 mmol) of1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 588 mg (87%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.24 (1H, d, J=8 Hz), 1.40-1.50 (5H, m) 1.67 (2H,td, J=10 Hz, 9 Hz), 1.81-1.89 (2H, m), 1.91-2.09 (2H, m), 2.40-2.50 (4H,m), 6.53 (1H, t, J=3 Hz), 7.46 (1H, s), 12.03 (1H, s)

REFERENCE EXAMPLE 54 1-[(4-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of 4-pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 609 mg (77%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.53 (3H, m), 1.62-1.77 (3H, m), 1.92-2.03 (2H,m), 2.13-2.21 (2H, m), 3.75 (3H, s), 6.29 (1H, br-s), 7.62 (2H, dd, J=5Hz, 2 Hz), 8.76 (2H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 55 1-[(4-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

609 mg (2.3 mmol) of 1-[(4-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 522 mg (97%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.33 (1H, m), 1.46-1.59 (5H, m), 1.70-1.80(2H, m), 2.09-2.15 (2H, m), 7.73 (2H, dd, J=5 Hz, 2 Hz), 8.51 (1H, s),8.72 (2H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 561-[(1H-Pyrrol-2-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

278 mg (2.5 mmol) of 2-pyrrolecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 534 mg (85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.45 (2H, m), 1.45-1.53 (2H, m), 1.62-1.72 (2H,m), 1.93 (2H td, J=13 Hz, 4 Hz), 2.08-2.19 (2H, m), 3.70 (3H, s), 6.05(1H, br-s), 6.23-6.25 (1H, m), 6.61 (1H, d, J=2 Hz), 6.94 (1H, d, J=2Hz)

REFERENCE EXAMPLE 571-[(1H-Pyrrol-2-ylcarbonyl)amino]cyclohexanecarboxylic acid

500 mg (2 mmol) of1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 338 mg (71%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.20-1.31 (1H, m), 1.52 (5H, br-s), 1.70-1.80 (2H,m), 2.04-2.18 (2H, m), 6.08 (1H, dd, J=4 Hz, 2 Hz), 6.85-6.89 (2H, m),7.59 (1H, s), 11.39 (1H, s), 12.09 (1H, br-s)

REFERENCE EXAMPLE 581-[[(6-Hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 6-hydroxy-2-pyridinecarboxylic acid was used insteadof 3-furancarboxylic acid in the process according to Reference example15 to obtain 1.32 g (47%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (1H, m), 1.65 (5H, m), 1.96 (2H, td, J=12Hz, 4 Hz), 2.10-2.21 (2H, m), 3.73 (3H, s), 6.71 (1H, d, J=9 Hz), 7.20(1H, d, J=7 Hz), 7.62 (1H, dd, J=9 Hz, 7 Hz), 8.00 (1H, s)

REFERENCE EXAMPLE 591-[[(6-Hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

1.32 mg (4.7 mmol) of1-[[(6-hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 1.16 g (88%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.39-1.50 (1H, m), 1.39-1.50 (2H, m), 1.51-1.63(3H, m), 1.70-1.82 (2H, m), 2.01-2.12 (2H, d, m), 6.78 (1H, d, J=8 Hz),7.32 (1H, br-s), 7.74 (1H, t, J=8 Hz), 8.18 (1H, s)

REFERENCE EXAMPLE 601-[[(2-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 2-hydroxynicotinic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 697 mg (25%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.38 (1H, m), 1.50-1.62 (2H, m), 1.64-1.74 (3H,m), 1.82-1.93 (2H, m), 2.15-2.24 (2H, m), 3.74 (3H, s), 6.53 (1H, t, J=7Hz), 7.49 (1H, d, J=7 Hz), 8.57 (1H, d, J=7 Hz), 10.04 (1H, s)

REFERENCE EXAMPLE 611-[[(2-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

698 mg (2.5 mmol) of1-[[(2-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 580 mg (83%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.21-1.31 (1H, m), 1.38-1.41 (2H, m), 1.59 (3H, d,J=10 Hz), 1.67-1.72 (2H, m), 1.98-2.04 (2H, m), 6.49 (1H, t, J=7 Hz),7.73 (1H, br-s), 8.28 (1H, d, J=7 Hz), 10.21 (1H, s), 12.19 (1H, s),12.53 (1H, br-s)

REFERENCE EXAMPLE 621-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 6-hydroxynicotinic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 869 mg (31%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (1H, m), 1.43-1.58 (2H, m), 1.61-1.75 (3H,m), 1.89-1.99 (2H, m), 2.11-2.19 (2H, m), 3.74 (3H, s), 6.43 (1H, s),6.53 (1H, d, J=10 Hz), 7.82 (1H, dd, J=10 Hz, 2 Hz), 8.05 (1H, d, J=2Hz)

REFERENCE EXAMPLE 631-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

869 mg (3.1 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 818 mg (94%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.19-1.31 (1H, m), 1.42-1.57 (5H, m), 1.67-1.78(2H, m), 2.01-2.11 (2H, m), 6.34 (1H, d, J=10 Hz), 7.84 (1H, dd, J=10Hz, 2 Hz), 7.95 (1H, s), 8.05 (1H, d, J=2 Hz), 11.90-12.18 (2H, m)

REFERENCE EXAMPLE 641-[[1-Oxo-3-(2-furanyl)propyl]amino]cyclohexanecarboxylic acid methylester

420 mg (3 mmol) of 3-(2-furyl)propionic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 478 mg (57%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.38 (3H, m), 1.57-1.65 (3H, m), 1.78-1.85 (2H,m), 1.96-2.01 (2H, m), 2.56 (2H, t, J=7 Hz), 2.98 (2H, t, J=7 Hz), 3.69(3H, s), 5.56 (1H, br-s), 6.06 (1H, dd, J=3 Hz, 2 Hz), 6.29 (1H, dd, J=3Hz, 2 Hz), 7.31 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 651-[[[1-(2-Propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

646 mg (3 mmol) of 1-(2-propoxycarbonyl)nipecotic acid was used insteadof 3-furancarboxylic acid in the process according to Reference example15 to obtain 979 mg (92%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24 (6H, d, J=6 Hz), 1.25-1.44 (3H, m), 1.56-1.70(5H, m), 1.79-1.90 (4H, m), 1.98-2.07 (2H, m), 2.26-2.34 (1H, m),2.75-2.88 (2H, m), 3.69 (3H, s), 4.17 (2H, br-s), 4.86-4.96 (1H, m),5.58 (1H, s)

REFERENCE EXAMPLE 661-[[[1-(2-Propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

979 mg (2.76 mmol) of1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 940 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.28 (7H, m), 1.34-1.39 (3H, m), 1.62-1.71 (6H,m), 1.85-1.91 (4H, m), 2.05-2.09 (2H, m), 2.33-2.36 (1H, m), 2.74-2.84(2H, m), 4.21 (1H, br-s), 4.91 (1H, q, J=7 Hz), 5.67 (1H, s)

REFERENCE EXAMPLE 671-[[[1-(Ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

604 mg (3 mmol) of 1-ethoxycarbonylnipecotic acid was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 976 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.25-1.42 (3H, m) 1.55-1.70(3H, m), 1.81-1.86 (4H, m), 2.01-2.05 (3H, m), 2.26-2.32 (1H, m),2.80-2.89 (2H, m), 3.69 (3H, s), 4.08-4.23 (3H, m), 4.13 (2H, q, J=7Hz), 5.54 (1H, br-s)

REFERENCE EXAMPLE 681-[[[1-(Ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

976 mg (2.87 mmol) of1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 935 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.42 (3H, m), 1.62-1.72(5H, m), 1.85-1.91 (4H, m), 2.06-2.09 (2H, m), 2.34-2.39 (1H, m),2.79-2.90 (2H, m), 4.10-4.25 (3H, m), 4.13 (2H, q, J=7 Hz), 5.69 (1H, s)

REFERENCE EXAMPLE 691-[[[1-(2-Furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

670 mg (3 mmol) of 1-(2-furanylcarbonyl)piperidine-4-carboxylic acid wasused instead of 3-furancarboxylic acid in the process according toReference example 15 to obtain 910 mg (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.43 (3H, m), 1.53-1.69 (3H, m), 1.74-1.90 (4H,m), 1.91-2.05 (4H, m), 2.43-2.48 (1H, m), 2.89-3.21 (2H, m), 3.79 (3H,s), 4.40-4.56 (2H, m), 5.58 (1H, br-s), 6.47 (1H, dd, J=3 Hz, 1 Hz),6.95 (1H, dd, J=3 Hz, 1 Hz), 7.48 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 701-[[[1-(2-Furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

910 mg (2.4 mmol) of1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 196 mg (23%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.17-1.25 (1H, m), 1.40-1.58 (7H, m) 1.58-1.62 (2H,m), 1.73-1.76 (2H, m), 1.93-1.96 (2H, m), 2.51-2.61 (1H, m), 2.80-3.11(2H, m), 4.22-4.33 (2H, m), 6.61 (1H, dd, J=3 Hz, 1 Hz), 6.95 (1H, dd,J=3 Hz, 1 Hz), 7.78 (1H, s), 7.82 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 711-[[[(2-Furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidmethyl ester

507 mg (3 mmol) of N-(2-furanylcarbonyl)glycine was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 781 mg (88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.38 (1H, m), 1.39-1.50 (2H, m), 1.58-1.69 (3H,m), 1.85 (2H, td, J=9 Hz, 4 Hz), 2.02-2.10 (2H, m), 3.70 (3H, s), 4.15(2H, d, J=6 Hz), 6.51 (1H, dd, J=2 Hz, 1 Hz), 6.67 (1H, s), 7.13 (2H,m), 7.47 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 721-[[[(2-Furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acid

781 mg (2.7 mmol) of1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference example 16 to obtain 320 mg (41%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.12-1.25 (1H, m), 1.39-1.58 (5H, m), 1.64 (2H, td,J=13 Hz, 4 Hz), 1.90-2.02 (2H, m), 3.88 (2H, d, J=6 Hz), 6.62 (1H, dd,J=3 Hz, 1 Hz), 7.13 (1H, dd, J=3 Hz, 1 Hz), 7.84 (1H, d, J=1 Hz), 7.87(1H, s), 8.38 (1H, d, J=6 Hz)

REFERENCE EXAMPLE 731-[[(Benzoylamino)acetyl]amino]cyclohexanecarboxylic acid methyl ester

538 mg (3 mmol) of N-benzoylglycine was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 812 mg (81%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.48 (2H, td, J=9 Hz, 4 Hz)1.58-1.71 (3H, m), 1.84 (2H, dt, J=9 Hz, 4 Hz), 2.02-2.10 (2H, m), 3.70(3H, s), 4.21 (2H, d, J=7 Hz), 7.08 (1H, br-s), 7.26-7.46 (3H, m), 7.54(1H, td, J=8 Hz, 1 Hz), 7.84 (2H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 741-[[(Benzoylamino)acetyl]amino]cyclohexanecarboxylic acid

812 mg (2.4 mmol) of1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid methyl esterwas used instead of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference example 16 toobtain 724 mg (93%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.09-1.67 (8H, m), 1.96 (2H, d, J=11 Hz), 3.93 (2H,d, J=6 Hz), 7.47 (2H, td, J=6 Hz, 1 Hz), 7.52-7.55 (1H, m), 7.86-7.89(3H, m), 8.64 (1H, t, J=6 Hz)

REFERENCE EXAMPLE 751-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methylester

3.67 g (30 mmol) of dimethylaminopyridine was added to a solution of65.48 g (0.3 mol) of di-t-butyl dicarbonate in 300 ml of anhydroustoluene, and the mixture was stirred at room temperature for 15 minutes.A solution of 47.17 g (0.3 mol) of 1-aminocyclohexanecarboxylic acidmethyl ester in 100 ml of anhydrous toluene was added to the reactionsolution, and the mixture was stirred at room temperature for 1 hour.After 60.71 g (0.6 mol) of triethylamine and 44.1 g (0.45 mol) offurfuryl alcohol were further added thereto, the mixture was heatedunder reflux for 3 hours. The reaction solution was returned to roomtemperature and concentrated under reduced pressure. The obtainedresidue was triturated in a mortal and stirred in a mixed solution of 5ml of hydrochloric acid and 3 litres of water for 18 hours. The obtainedcrystal was collected by filtration to give 74.37 g (88%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.23-1.36 (1H, m), 1.38-1.51 (2H, m), 1.55-1.65 (3H,m), 1.80-1.88 (2H, m), 1.93-2.04 (2H, m), 3.71 (3H, br-s), 4.93 (1H,br-s), 5.04 (2H, s), 6.36 (1H, dd, J=3 Hz, 2 Hz), 6.41 (1H, d, J=3 Hz),7.43 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 761-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid

28.13 g (0.1 mol) of1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methylester was added to a mixture solution of 150 ml of 2N-sodium hydroxideaqueous solution and 200 ml of tetrahydrofuran, and the mixture wasrefluxed under heating for 18 hours. After the solvent was distilledoff, water was added to the residue and the mixture was washed withdiethyl ether. After potassium hydrogensulfate was added to the aqueouslayer to acidify it, the layer was extracted with ethyl acetate twice.After the organic layer was washed with saturated brine and dried withanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure. Diisopropyl ether was added to the residue, and the mixturewas stirred for 18 hours. The obtained crystal was collected byfiltration to give 19.89 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.37 (1H, m), 1.38-1.52 (2H, m), 1.59-1.71 (3H,m), 1.82-1.93 (2H, m), 1.99-2.12 (2H, m), 4.99 (1H, br-s), 5.07 (2H, s),6.37 (1H, dd, J=3 Hz, 2 Hz), 6.42 (1H, d, J=3 Hz), 7.43 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 771-[[(4-Phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 366 mg (3 mmol) of N,N-dimethylaminopyridine and 6.99 g(30 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inmethylene chloride was added to a solution of 6.55 g (30 mmol) ofdi-t-butyl dicarbonate in 150 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 6.07 mg (60 mmol) of triethylamine and 5.11 g (33 mmol) of1-phenylpiperazine in methylene chloride was added thereto, and themixture was stirred at room temperature overnight. The reaction solutionwas concentrated, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the obtained crystal was washed with diethyl ether togive 8.88 g (70%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.37 (1H, m), 1.42-1.51 (2H, m), 1.50-1.69 (3H,m), 1.82-1.91 (2H, m), 2.03-2.10 (2H, m), 3.17 (4H, t, J=5 Hz), 3.54(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.89-6.94 (3H, m),7.26-7.35 (7H, m)

REFERENCE EXAMPLE 781-[[(4-Phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid

8.88 g (21 mmol) of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester obtained in Reference example 77 was dissolved in 200ml of methanol, 900 mg of 10% palladium-carbon was added thereto, andthe mixture was stirred under a hydrogen atmosphere at room temperatureovernight. After the reaction solution was filtered, the filtrate wasconcentrated under reduced pressure to obtain 6.96 g (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.22-1.30 (1H, m), 1.36-1.42 (2H, m), 1.50-2.05 (5H,m), 2.06-2.14 (2H, m), 3.24 (4H, t, J=5 Hz), 4.61 (4H, t, J=5 Hz), 4.51(1H, br-s), 6.92-6.95 (2H, m), 7.28-7.32 (3H, m)

REFERENCE EXAMPLE 791-[[[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

3.43 g (21 mmol) of 1-(2-pyridinyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 7.33 g (87%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26-1.35 (1H, m), 1.42-1.53 (2H, m), 1.60-1.68 (3H,m), 1.83-1.92 (2H, m), 2.02-2.10 (2H, m), 3.52 (4H, t, J=5 Hz), 3.57(4H, t, J=5 Hz), 4.58 (1H, br-s), 5.15 (2H, s), 6.63 (1H, d, J=8 Hz),6.67 (1H, td, J=8 Hz, 1 Hz), 7.25-7.34 (5H, m), 7.51 (1H, td, J=8 Hz, 1Hz), 8.20 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 801-[[[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

7.33 g (17.4 mmol) of1-[[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 5.75 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.43 (2H, m), 1.60-1.72 (4H, m), 1.89-1.99 (2H,m), 2.06-2.13 (2H, m), 3.61 (4H, t, J=5 Hz), 3.66 (4H, t, J=5 Hz), 4.61(1H, br-s), 6.65 (1H, dd, J=8 Hz, 1 Hz), 6.69 (1H, td, J=8 Hz, 1 Hz),7.52 (1H, td, J=8 Hz, 1 Hz), 8.20 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 811-[[[4-(4-Fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

3.78 g (21 mmol) of 1-(4-fluorophenyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 4.48 g (51%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.35 (1H, m), 1.40-1.51 (2H, m), 1.55-1.70 (3H,m), 1.85-1.93 (2H, m), 2.02-2.09 (2H, m), 3.07 (4H, t, J=5 Hz), 3.53(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.87 (2H, ddd, J=9 Hz, 6Hz, 2 Hz), 6.98 (2H, ddd, J=9 Hz, 6 Hz, 2 Hz), 7.25-7.35 (5H, m)

REFERENCE EXAMPLE 821-[[[4-(4-Fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

4.48 g (10 mmol) of1-[[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 3.56 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.43 (3H, m), 1.60-1.75 (3H, m), 1.89-2.01 (2H,m), 2.05-2.13 (2H, m), 3.14 (4H, t, J=5 Hz), 3.61 (4H, t, J=5 Hz), 4.55(1H, br-s), 6.89 (2H, ddd, J=8 Hz, 5 Hz, 2 Hz), 6.99 (2H, ddd, J=8 Hz, 5Hz, 2 Hz)

REFERENCE EXAMPLE 831-[[[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

4.83 g (21 mmol) of 1-[3-(trifluoromethyl)phenyl]piperazine was usedinstead of 1-phenylpiperazine in the process according to Referenceexample 77 to obtain 7.54 g (77%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.37 (1H, m), 1.42-1.53 (2H, m), 1.59-1.70 (3H,m), 1.85-1.94 (2H, m), 2.02-2.10 (2H, m), 3.21 (4H, t, J=5 Hz), 3.55(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 7.05 (1H, dd, J=8 Hz, 2Hz), 7.09 (1H, s), 7.12 (1H, dd, J=8 Hz, 2 Hz), 7.25-7.40 (6H, m)

REFERENCE EXAMPLE 841-[[[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

7.54 g (15.4 mmol) of1-[[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 5.92 g (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.44 (2H, m), 1.60-1.75 (4H, m), 1.91-2.00 (2H,m), 2.05-2.14 (2H, m), 3.30 (4H, t, J=5 Hz), 3.63 (4H, t, J=5 Hz), 4.63(1H, br-s), 7.07 (1H, d, J=8 Hz), 7.11 (1H, s), 7.15 (1H, d, J=8 Hz),7.38 (1H, t, J=8 Hz)

REFERENCE EXAMPLE 851-[[(4-Cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.66 g (15.8 mmol) of 1-(cyclohexyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 3.21 g (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.45 (3H, m), 1.39-1.50 (3H, m), 1.51-1.67 (6H,m), 1.89-1.90 (6H, m), 2.01-2.07 (2H, m), 2.22-2.30 (1H, m), 2.54 (4H,t, J=5 Hz), 3.38 (4H, t, J=5 Hz), 4.53 (1H, br-s), 5.14 (2H, s),7.25-7.34 (5H, m)

REFERENCE EXAMPLE 861-[[(4-Cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid

3.21 g (7.5 mmol) of1-[[(4-cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 2.53 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.05-1.19 (1H, m), 1.10-1.19 (2H, m), 1.20-1.32 (2H,m), 1.58-1.97 (13H, m), 2.03-2.12 (2H, m), 2.35-2.44 (1H, m), 2.67 (4H,t, J=5 Hz), 3.48 (4H, t, J=5 Hz), 4.59 (1H, br-s)

REFERENCE EXAMPLE 871-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g(9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inmethylene chloride was added to a solution of 2.03 g (9.3 mmol) ofdi-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of1-(benzoyl)piperazine in methylene chloride was added thereto, and themixture was stirred at room temperature overnight. After the reactionsolution was concentrated, the residue was dissolved in ethyl acetateand successively washed with water, a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with anhydrous sodiumsulfate. After the solvent was distilled off under reduced pressure, theobtained crystal was washed with diethyl ether to give 3.60 g (86%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H,m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m), 3.28-3.57 (6H, m), 3.66-3.85(2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48(6H, m)

REFERENCE EXAMPLE 881-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid

3.60 g (8 mmol) of1-[[(4-benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 2.88 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.42 (2H, m), 1.59-1.74 (2H, m), 1.85-2.10 (6H,m), 3.42-3.58 (6H, m), 3.70-3.87 (2H, m), 4.60 (1H, br-s), 7.39-7.47(5H, m)

REFERENCE EXAMPLE 891-[[[4-(Phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester

5.82 g (33 mmol) of 4-(phenylmethyl)piperazine was used instead of1-phenylpiperazine and 5.14 g (30 mmol) of 1-aminocyclohexanecarboxylicacid ethyl ester was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 77 toobtain 7.62 g (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.24-1.39 (1H, m) 1.40-1.49(2H, m), 1.55-1.64 (3H, m), 1.80-1.89 (2H, m), 1.97-2.04 (2H, m), 2.44(4H, t, J=5 Hz), 3.39 (4H, t, J=5 Hz), 3.52 (2H, s), 4.17 (2H, q, J=7Hz), 4.50 (1H, br-s), 7.23-7.30 (1H, m), 7.30-7.37 (4H, m)

REFERENCE EXAMPLE 901-[[[4-(Phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

600 ml of 1N aqueous sodium hydroxide solution was added to a solutionof 7.62 g (20 mmol) of1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in 300 ml of ethanol, and the mixture was heated underreflux for 2 hours. After ether was added to the reaction solution andthe mixture was washed, the aqueous layer was neutralized byconcentrated hydrochloric acid and extracted with ethyl acetate. Afterthe obtained organic layer was washed with saturated brine, the layerwas dried with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain 2.90 g (42%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.38 (2H, m), 1.60-1.71 (4H, m), 1.88-1.98 (2H,m), 2.01-2.10 (2H, m), 2.49 (4H, t, J=5 Hz), 3.45 (4H, t, J=5 Hz), 3.55(2H, s), 4.43 (1H, br-s), 7.24-7.34 (5H, m)

REFERENCE EXAMPLE 911-[[4-(1-Oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.40 g (11 mmol) of 1-(1-oxo-3-phenylpropyl)piperazine was used insteadof 1-(benzoyl)piperazine in the process according to Reference example87 to obtain 3.53 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.39 (1H, m), 1.40-1.49 (2H, m), 1.58-1.67 (3H,m), 1.84-1.93 (2H, m), 2.00-2.07 (2H, m), 2.62 (2H, t, J=6 Hz), 2.98(2H, t, J=6 Hz), 3.25-3.33 (6H, m), 3.59-3.65 (2H, m), 4.52 (1H, br-s),5.14 (2H, br-s), 7.18-7.23 (4H, m), 7.28-7.34 (6H, m)

REFERENCE EXAMPLE 921-[[[4-(1-Oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

3.53 g (7.4 mmol) of1-[[[4-(1-oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 2.87 g (quantitative) of the title compound.

1H-NMR (CDC₃, δ): 1.28-1.53 (3H, m), 1.57-1.70 (3H, m), 1.84-1.97 (2H,m), 2.00-2.08 (2H, m), 2.63 (2H, t, J=6 Hz), 2.98 (2H, m, J=6 Hz),3.33-3.41 (6H, m), 3.67-3.71 (2H, m), 4.78 (1H, br-s), 7.18-7.25 (3H,m), 7.27-7.34 (2H, m)

REFERENCE EXAMPLE 931-[[[4-(Phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

1.23 g (6 mmol) of 1-(phenylacetyl)piperazine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to Referenceexample 87 to obtain 2.39 g (87%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.36 (1H, m), 1.37-2.06 (2H, m), 1.55-1.66 (3H,m), 1.83-1.92 (2H, m), 1.98-2.03 (2H, m), 3.20 (2H, t, J=5 Hz), 3.31(2H, t, J=5 Hz), 3.41 (2H, t, J=5 Hz), 3.63 (2H, t, J=5 Hz), 3.74 (2H,s), 4.49 (1H, br-s), 5.12 (2H, s), 7.24-7.32 (10H, m)

REFERENCE EXAMPLE 941-[[[4-(Phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

2.39 g (5.2 mmol) of1-[[[4-(phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 1.94 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.39 (3H, m), 1.58-1.70 (3H, m), 1.86-1.96 (2H,m), 1.99-2.07 (2H, m), 3.26 (2H, t, J=5 Hz), 3.38 (2H, t, J=5 Hz), 3.50(2H, t, J=5 Hz), 3.72 (2H, t, J=5 Hz), 3.76 (2H, s), 4.50 (1H, br-s),7.23-7.30 (3H, m), 7.30-7.35 (2H, m)

REFERENCE EXAMPLE 951-[(1-Piperidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

1.34 g (15.8 mmol) of piperidine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to Referenceexample 87 to obtain 4.59 g (89%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.34 (1H, m), 1.40-1.65 (11H, m), 1.82-1.90 (2H,m), 2.02-2.08 (2H, m), 3.32 (4H, t, J=5 Hz), 4.53 (1H, br-s), 5.14 (2H,s), 7.29-7.35 (5H, m)

REFERENCE EXAMPLE 961-[(1-Piperidinylcarbonyl)amino]cyclohexanecarboxylic acid

4.59 g (12 mmol) of1-[(1-piperidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 3.05 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (4H, m), 1.56-1.70 (8H, m), 1.85-1.96 (2H,m), 2.05-2.13 (2H, m), 3.89 (4H, t, J=5 Hz), 4.51 (1H, br-s)

REFERENCE EXAMPLE 971-[(1-Pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

1.12 g (15.8 mmol) of pyrrolidine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to Referenceexample 87 to obtain 3.23 g (65%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.33 (1H, m), 1.42-1.51 (2H, m), 1.51-1.68 (3H,m), 1.82-1.95 (2H, m), 1.89 (4H, t, J=7 Hz), 2.02-2.10 (2H, m), 3.35(4H, t, J=7 Hz), 4.33 (1H, br-s), 5.16 (2H, s), 7.26-7.36 (5H, m)

REFERENCE EXAMPLE 981-[(1-Pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid

3.23 g (9.8 mmol) of1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 2.35 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.42 (3H, m), 1.58-1.72 (3H, m), 1.88-2.00 (6H,m), 2.05-2.14 (2H, m), 3.40 (4H, t, J=6 Hz), 4.34 (1H, br-s)

REFERENCE EXAMPLE 991-[[(2-Oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 183 mg (1.5 mmol) of N,N-dimethylaminopyridine and 3.50 g(15 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester intoluene was added to a solution of 3.27 g (15 mmol) of di-t-butyldicarbonate in 60 ml of toluene, and the mixture was stirred at roomtemperature for 30 minutes. Thereafter, 3.04 g (30 mmol) oftriethylamine, 1.83 g (15 mmol) of N,N-dimethylaminopyridine and 1.56 g(15.8 mmol) of 2-piperidone were added thereto, and the mixture wasrefluxed under heating overnight. Ethyl acetate was added to thereaction solution and the mixture was successively washed with water, a10% aqueous potassium hydrogensulfate solution, a saturated aqueoussodium hydrogencarbonate solution and saturated brine, followed bydrying with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure and the obtained residue was purified by silicagel chromatography to give 4.10 g (76%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-1.30 (1H, m), 1.42-1.53 (2H, m), 1.61-1.69 (3H,m), 1.78-1.90 (6H, m), 2.06-2.15 (2H, m), 2.54 (2H, t, J=6 Hz), 3.73(2H, t, J=6 Hz), 5.16 (2H, s), 7.27-7.35 (5H, m), 9.85 (1H, br-s)

REFERENCE EXAMPLE 1001-[[(2-Oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acid

4.10 g (11.4 mmol) of1-[[1-(2-oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 2.95 g (96%) of the title compound.

1H-NMR (CDCl₃₁ δ): 1.24-1.35 (1H, m), 1.45-1.64 (2H, m), 1.50-1.71 (3H,m), 1.82-1.92 (6H, m), 2.12-2.16 (2H, m), 2.58 (2H, t, J=6 Hz), 3.80(2H, t, J=6 Hz), 9.96 (1H, br-s)

REFERENCE EXAMPLE 1011-[(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

3.00 g (21 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane was used instead of1-(benzoyl)piperazine in the process according to Reference example 87to obtain 5.70 g (71%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.34 (1H, m), 1.40-1.48 (2H, m), 1.59-1.67 (3H,m), 1.69 (4H, t, J=6 Hz), 1.84-1.93 (2H, m), 2.00-2.08 (2H, m), 3.47(4H, t, J=6 Hz), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s), 7.27-7.36(5H, m)

REFERENCE EXAMPLE 1021-[(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid

5.70 g (14.2 mmol) of1-[(1,4-dioxa-8-azaspiro[4,5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 4.38 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (3H, m), 1.60-1.77 (3H, m), 1.75 (4H, t,J=6 Hz), 1.88-2.01 (2H, m), 2.05-2.14 (2H, m), 3.54 (4H, t, J=6 Hz),3.99 (4H, s), 4.55 (1H, br-s)

REFERENCE EXAMPLE 1031-[[[(1,3-Dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.46 g (21 mmol) of 2-[(methylamino)methyl]-1,3-dioxolane was usedinstead of 1-(benzoyl)piperazine in the process according to Referenceexample 87 to obtain 6.05 g (80%) of the title compound.

1H-NMR (CDCl₃₁ δ): 1.22-1.34 (1H, m), 1.39-1.50 (2H, m), 1.59-1.68 (2H,m), 1.68-1.74 (3H, m), 1.82-1.91 (2H, m), 2.00-2.08 (2H, m), 3.44-3.50(4H, m), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s), 7.27-7.36 (5H, m)

REFERENCE EXAMPLE 1041-[[[(1,3-Dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid

6.05 g (16 mmol) of1-[[[(1,3-dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 4.45 g (97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (3H, m), 1.60-1.75 (5H, m), 1.88-1.97 (2H,m), 2.04-2.13 (2H, m), 3.48-3.59 (4H, m), 3.99 (4H, s), 4.53 (1H, br-s)

REFERENCE EXAMPLE 1051-[[(1,3-Dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.50 g (21 mmol) of isoindoline was used instead of1-(benzoyl)piperazine in the process according to Reference example 87to obtain 5.95 g (79%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.45-1.70 (5H, m), 1.89-1.97 (2H,m), 2.07-2.16 (2H, m), 4.48 (1H, br-s), 4.73 (4H, s), 5.17 (2H, s),7.25-7.31 (7H, m), 7.31-7.36 (2H, m)

REFERENCE EXAMPLE 1061-[[(1,3-Dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid

5.95 g (15.8 mmol) of1-[[(1,3-dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 3.09 g (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.30 (1H, m), 1.35-1.48 (2H, m), 1.59-1.76 (3H,m), 1.96-2.05 (2H, m), 2.10-2.17 (2H, m), 4.40 (1H, br-s), 4.78 (4H,br-s), 7.24-7.35 (4H, m)

REFERENCE EXAMPLE 1071-[[(2-Oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added toa solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml ofchloroform, and the mixture was stirred at 60° C. for 4 days. Thereaction solution was successively washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, and the mixture wasdried with anhydrous sodium sulfate. The solvent was distilled off underreduced pressure and the obtained crystal was washed with diethyl etherto obtain 2.64 g (82%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.31 (1H, m), 1.44-1.54 (2H, m), 1.60-1.68 (3H,m), 1.81-1.88 (2H, m), 2.08-2.16 (2H, m), 3.48 (2H, t, J=7 Hz), 3.93(2H, t, J=7 Hz), 4.75 (1H, br-s), 5.17 (2H, s), 7.26-7.36 (5H, m), 8.45(1H, br-s)

REFERENCE EXAMPLE 1081-[[(2-Oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acid

2.64 g (7.6 mmol) of1-[[(2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 1.95 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.41-1.70 (5H, m), 1.83-1.92 (2H,m), 2.11-2.20 (2H, m), 3.54 (2H, t, J=8 Hz), 4.01 (2H, t, J=8 Hz), 4.92(1H, br-s), 8.53 (1H, br-s)

REFERENCE EXAMPLE 1091-[[(3-Methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

1.83 g (12.9 mmol) of methyl iodide was added to a solution of 1.50 g(4.3 mmol) of1-[[(2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 1.78 g (12.9 mmol) of potassium carbonate in 100ml of acetonitrile, and the mixture was refluxed under heatingovernight. The reaction solution was concentrated, ethyl acetate wasadded thereto, and the mixture was successively washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel chromatographyto obtain 710 mg (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-1.30 (1H, m), 1.42-1.56 (2H, m), 1.61-1.69 (3H,m), 1.79-1.88 (2H, m), 2.08-2.17 (2H, m), 2.86 (3H, s), 3.40 (2H, t, J=8Hz), 3.81 (2H, t, J=8 Hz), 5.17 (2H, s), 7.30-7.36 (5H, m), 8.55 (1H,br-s)

REFERENCE EXAMPLE 1101-[[(3-Methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid

710 mg (2 mmol) of1-[[(3-methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 78 toobtain 539 mg (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.33 (1H, m), 1.42-1.53 (2H, m), 1.61-1.70 (3H,m), 1.82-1.89 (2H, m), 2.11-2.20 (2H, m), 2.89 (3H, s), 3.46 (2H, dd,J=10 Hz, 8 Hz), 3.91 (2H, dd, J=10 Hz, 8 Hz), 8.66 (1H, br-s)

REFERENCE EXAMPLE 1111-[[(2,5-Dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid methyl ester

472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and311 mg (4.5 mmol) of 2,5-dihydropyrrole was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 698 mg (92%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.42-1.53 (2H, m), 1.53-1.69 (3H,m), 1.82-1.92 (2H, m), 2.01-2.10 (2H, m), 3.73 (3H, s), 4.18 (4H, s),4.31 (1H, s), 5.82 (2H, s)

REFERENCE EXAMPLE 1121-[[(2,5-Dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid

698 mg (2.8 mmol) of1-[[(2,5-dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference example 90 toobtain 453 mg (69%) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.73 (6H, m), 1.92-2.22 (2H, m), 2.24-2.36 (2H,m), 4.23 (4H, br-s), 4.23 (1H, br-s), 5.87 (2H, br-s)

REFERENCE EXAMPLE 1131-[(1H-Pyrrol-1-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

1 g (6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and512 mmol (7.6 mmol) of pyrrole was used instead of 1-phenylpiperazine inthe process according to Reference example 77 to obtain 1.52 g (95%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.36-1.57 (3H, m), 1.65-1.74 (3H, m), 1.91-2.02 (2H,m), 2.08-2.19 (2H, m), 3.74 (3H, s), 5.58 (1H, s), 6.28 (2H, dd, J=2 Hz,1 Hz), 7.19 (2H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1141-[(1H-Pyrrol-1-ylcarbonyl)amino]cyclohexanecarboxylic acid

1.52 g (6 mmol) of1-[[(1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference example 90 toobtain 839 mg (58%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.15-1.61 (4H, m), 1.69-1.81 (2H, m), 1.83-1.98(2H, m), 2.08-2.19 (2H, m), 6.12 (2H, s), 6.21 (1H, d, J=2 Hz), 7.42(2H, d, J=2 Hz), 7.88 (1H, dr-s)

REFERENCE EXAMPLE 1151-[(3-Thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid

A solution of 78 mg (0.6 mmol) of N,N-dimethylaminopyridine and 1 g(6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester inmethylene chloride was added to a solution of 1.39 mg (6.36 mmol) ofdi-t-butyl dicarbonate in 10 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 1.29 g (12.7 mmol) of triethylamine and 680 mg (7.6 mmol) ofthiazolidine in methylene chloride was added thereto, and the mixturewas stirred at room temperature overnight. After the reaction mixturewas concentrated, the residue was dissolved in ethyl acetate, and themixture was washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution, andthen saturated brine, followed by drying with anhydrous sodium sulfate.After the solvent was distilled off under reduced pressure,tetrahydrofuran and a 1N aqueous sodium hydroxide solution were added tothe residue, and the mixture was heated under reflux for 3 hours. Afterether was added to the reaction solution to wash it, the aqueous layerwas neutralized by concentrated hydrochloric acid and extracted withethyl acetate. After the obtained organic layer was washed withsaturated brine, the layer was dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain 1.1 g (66%)of the title compound.

1H-NMR (DMSO-d₆, δ): 1.08-1.25 (1H, m), 1.36-1.69 (6H, m), 1.82-2.01(3H, m), 2.93 (2H, t, J=7 Hz), 3.59 (2H, t, J=7 Hz), 4.43 (2H, s), 6.44(1H, s), 11.99 (1H, br-s)

REFERENCE EXAMPLE 1161-[[[(2-Furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and2.18 g (18 mmol) of (2-furanylmethyl)methylamine was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 4.27 g (78%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.47 (3H, m), 1.57-1.68 (3H, m), 1.80-1.85 (2H,m), 1.97-2.20 (2H, m), 2.94 (3H, s), 3.71 (3H, s), 4.42 (2H, s), 4.74(1H, s), 6.24 (1H, dd, J=3 Hz, 1 Hz), 6.34 (1H, dd, J=3 Hz, J=3 Hz, 2Hz), 7.37 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1171-[[[(2-Furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid

4.27 g (14 mmol) of1-[[[(2-furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference example 90 toobtain 3.47 g (84%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.12-1.23 (1H, m), 1.38-1.52 (5H, m), 1.58-1.64(2H, m), 1.80-2.22 (2H, m), 2.81 (3H, s), 4.42 (2H, s), 6.03 (1H, s),6.24 (1H, dd, J=3 Hz, 1 Hz), 6.40 (1H, dd, J=3 Hz, 2 Hz), 7.57 (1H, dd,J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1181-[[(Methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid methylester

472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and643 mg (6 mmol) of N-methylaniline was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 834 mg (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.12-1.28 (2H, m), 1.48-1.62 (4H, m), 1.64-1.70 (2H,m), 1.90-1.98 (2H, m), 3.25 (3H, s), 3.74 (3H, s), 4.49 (1H, s),7.26-7.36 (3H, m), 7.43-7.46 (2H, m)

REFERENCE EXAMPLE 1191-[[(Methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid

834 mg (2.87 mmol) of1-[[(methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference example 90 toobtain 464 mg (59%) of the title compound.

1H-NMR (CDC₃, δ): 0.96-1.05 (2H, m), 1.19-1.30 (1H, m), 1.50-1.60 (3H,m), 1.70-1.81 (2H, m), 1.96-2.02 (2H, m), 3.31 (3H, s), 4.30 (1H, s),7.26-7.33 (2H, m), 7.44 (1H, t, J=9 Hz), 7.51 (2H, t, J=9 Hz)

REFERENCE EXAMPLE 1201-[[[Methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and2.18 g (18 mmol) of N-methylbenzylamine was used instead of1-phenylpiperazine in the process according to Reference example 77 toobtain 4.27 g (78%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-1.38 (3H, m), 1.50-1.63 (3H, m), 1.78-1.85 (2H,m), 1.97-2.03 (2H, m), 2.94 (3H, s), 3.73 (3H, s), 4.49 (2H, s), 4.51(1H, s), 7.25-7.30 (3H, m), 7.35 (2H, dt, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 1211-[[[Methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic acid

4.27 g (14 mmol) of1-[[[methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference example 90 toobtain 3.54 g (86%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.16-2.04 (1H, m), 1.39-1.47 (5H, m), 1.58-1.65(2H, m), 1.97-2.22 (2H, m), 2.79 (3H, s), 4.44 (2H, s), 6.00 (1H, s),7.21-7.34 (5H, m)

REFERENCE EXAMPLE 1221-[[(2-Oxo-2H-pyran-5-yl)carbonyl]amino]cyclohexanecarboxylic acid

A solution of 2.37 g (10 mmol) of 5-coumarincarboxylic acidN-hydroxysuccinimide ester, 1.43 g (10 mmol) of1-aminocyclohexanecarboxylic acid and 3.04 g (30 mmol) of triethylaminein 20 ml of dimethylformamide was stirred overnight. Ethyl acetate wasadded to the reaction solution, and the mixture was washed with a 10%aqueous potassium hydrogensulfate solution and then saturated brine.After it was dried with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to obtain 1.42 g (60%) of the titlecompound.

1H-NMR (DMSO-d₆, δ): 1.30-1.44 (3H, m), 1.44-1.63 (3H, m), 1.95-2.09(4H, m), 5.26 (1H, d, J=9 Hz), 7.62 (1H, d, J=9 Hz) 8.28 (1H, d, J=15Hz), 9.68 (1H, d, J=15 Hz)

REFERENCE EXAMPLE 123 1-[(4-Fluorobenzoyl)amino]cyclohexanecarboxylicacid

A solution of 25.0 g (15.8 mmol) of 4-fluorobenzoyl chloride in 30 ml ofether was added dropwise to a mixture solution of 22.6 g (15.8 mmol) of1-aminocyclohexanecarboxylic acid and 25.0 g (23.7 mmol) of sodiumcarbonate in 100 ml of ether and 300 ml of water under ice-cooling, andthe mixture was stirred at room temperature overnight. After the etherlayer was separated, the aqueous layer was neutralized with concentratedhydrochloric acid under ice-cooling and the precipitated crystal wascollected by filtration to obtain 27.7 g (66%) of the title compound.

REFERENCE EXAMPLE 1241-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.36 g (8.44 mmol) of 4-(4-propylpiperazin-1-yl)benzoic acidhydrochloride was used instead of phenylacetyl chloride in the processaccording to Reference example 1 to obtain 1.79 g (46%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=7 Hz), 1.28-1.40 (1H, m), 1.45-1.61(4H, m), 1.61-1.72 (3H, m), 1.90-1.98 (2H, m), 2.15-2.23 (2H, m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.31 (4H,t, J=5 Hz), 5.16 (2H, s), 6.13 (1H, br-s), 6.89 (2H, d, J=8 Hz),7.25-7.33 (5H, m), 7.68 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1251-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid

1.79 g (3.86 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 2 to obtain 1.43 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, t, J=8 Hz), 1.39-1.61 (3H, m), 1.65-1.78(4H, m), 1.94-2.03 (3H, m), 2.21-2.41 (2H, m), 2.45-2.54 (2H, m),2.65-2.70 (4H, m), 3.27-3.35 (4H, m), 6.06 (1H, br-s), 6.85 (2H, d, J=8Hz), 7.65 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1261-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

1.00 g (3.57 mmol) of 4-(4-propylpiperazin-1-yl)benzoic acidhydrochloride was used instead of 3-furancarboxylic acid in the processaccording to Reference example 15 to obtain 602 g (44%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.31-1.40 (1H, m), 1.44-1.58(4H, m), 1.62-1.74 (3H, m), 1.88-1.96 (2H, m), 2.11-2.19 (2H, m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.30 (4H,t, J=5 Hz), 3.72 (3H, s), 6.12 (1H, br-s), 6.89 (2H, dd, J=2 Hz, 7 Hz),7.69 (2H, dd, J=2 Hz, 7 Hz)

REFERENCE EXAMPLE 1271-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester hydrochloride

1 ml of 4N hydrochloric acid/ethyl acetate solution was added to asolution of 120 mg (0.31 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 10 ml of ethyl acetate, and the mixture was stirredat room temperature for 30 minutes. The precipitated crystal wascollected by filtration to obtain 87 mg (66%) of the title compound.

1H-NMR (DMSO-d₆, δ): 0.91 (3H, t, J=8 Hz), 1.21-1.35 (1H, m), 1.47-1.62(5H, m), 1.70-1.81 (4H, m), 2.02-2.10 (2H, m), 3.01-3.14 (4H, m),3.15-3.28 (2H, m), 3.50-3.58 (2H, m), 3.82-4.02 (5H, m), 7.04 (2H, dd,J=2 Hz, 7 Hz), 7.79 (2H, dd, J=2 Hz, 7 Hz), 8.11 (1H, s)

REFERENCE EXAMPLE 1281-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride

3 ml of 4N hydrochloric acid was added to 600 mg (1.55 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester, and the mixture was refluxed under heating for 6hours. The precipitated crystal obtained by cooling it to roomtemperature was collected by filtration to obtain 258 mg (41%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=7 Hz), 1.31-1.43 (1H, m), 1.45-1.56(2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H, m), 2.16-2.25 (2H, m),2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m), 6.65 (1H,br-s), 6.92 (2H, d, J=8 Hz), 7.97 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1291-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester

741 mg (3.57 mmol) of 1-aminocyclohexanecarboxylic acid ethyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidmethyl ester hydrochloride and 1.00 g (3.57 mmol) of4-(4-propylpiperazin-1-yl)benzoic acid hydrochloride was used instead of3-furancarboxylic acid in the process according to Reference example 15to obtain 928 mg (65%) of the title compound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.24 (3H, t, J=7 Hz), 1.30-1.41(1H, m), 1.43-1.71 (7H, m), 1.88-1.97 (2H, m), 2.10-2.20 (2H, m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 3.31 (4H, t, J=5 Hz), 4.18 (4H,t, J=5 Hz), 4.20 (2H, q, J=7 Hz), 6.10 (1H, br-s), 6.89 (2H, dd, J=2 Hz,8 Hz), 7.69 (2H, dd, J=2 Hz, 8 Hz)

REFERENCE EXAMPLE 1301-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester hydrochloride

120 mg (0.3 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester was used instead of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference example 127 toobtain 114 mg (87%) of the title compound.

1H-NMR (DMSO-d₆, δ): 0.93 (3H, t, J=8 Hz), 1.11 (3H, t, J=7 Hz),1.23-1.32 (1H, m), 1.45-1.55 (5H, m), 1.68-1.80 (4H, m), 2.02-2.10 (2H,m), 3.03-3.18 (6H, m), 3.51-3.62 (2H, m), 3.95-4.04 (2H, m), 4.02 (2H,q, J=7 Hz), 7.04 (2H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 8.10 (1H, s)

REFERENCE EXAMPLE 1311-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride

800 mg (1.99 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester was used instead of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference example 128 toobtain 197 mg (24%) of the title compound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=7 Hz), 1.31-1.43 (1H, m) 1.45-1.56(2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H, m), 2.16-2.25 (2H, m),2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m), 6.65 (1H,br-s), 6.92 (2H, d, J=8 Hz), 7.97 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1322-(Phenylmethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 784 mg (3 mmol) of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid obtained in Referenceexample 2 in 20 ml of methylene chloride. After the mixture was stirredat room temperature for 4 hours, the reaction solution was concentratedunder reduced pressure, ethyl acetate was added thereto, and the mixturewas successively washed with water, a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtain625 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 1.48-1.51 (1H, m), 1.56-1.70 (3H, m), 1.70-1.79 (6H,m), 3.79 (2H, s), 7.28-7.36 (5H, m)

REFERENCE EXAMPLE 1332-(2-Phenylethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

826 mg (3 mmol) of 1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 764 mg(99%) of the title compound.

1H-NMR (CDCl₃, δ): 1.47-1.55 (4H, m), 1.57-1.78 (6H, m), 2.79 (2H, t,J=7 Hz), 3.02 (2H, t, J=7 Hz), 7.20-7.23 (3H, m), 7.28-7.31 (2H, m)

REFERENCE EXAMPLE 134 2-Phenyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

742 mg (3 mmol) of 1-[(benzoyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 633 mg (92%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.52-1.58 (1H, m), 1.63-1.78 (3H, m), 1.79-1.89 (6H,m), 7.47 (1H, td, J=7 Hz, 1 Hz), 7.49 (1H, td, J=7 Hz, 1 Hz), 7.56 (1H,td, J=7 Hz, 1 Hz), 8.02 (2H, m)

REFERENCE EXAMPLE 135 2-(4-Biphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

970 mg (3 mmol) of 1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 914 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.52 (2H, m), 1.63-1.71 (1H, m), 1.72-1.80 (2H, m),1.81-1.90 (5H, m), 7.39-7.42 (1H, m), 7.47-7.50 (2H, m), 7.63 (1H, dd,J=7 Hz, 1 Hz), 7.65 (1H, dd, J=7 Hz, 1 Hz), 7.71 (1H, d, J=7 Hz, 1 Hz),7.72 (1H, dd, J=7 Hz, 1 Hz), 8.07 (1H, dd, J=7 Hz, 1 Hz), 8.08 (1H, dd,J=7 Hz, 1 Hz)

REFERENCE EXAMPLE 136 2-(2-Naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

595 mg (2 mmol) of 1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 562 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.54-1.68 (1H, m), 1.69-1.76 (1H, m), 1.78-1.94 (8H,m), 7.26-7.62 (2H, m), 7.89 (1H, d, J=8 Hz), 7.92 (1H, dd, J=8 Hz, 1Hz), 7.95 (1H, dd, J=8 Hz, 1 Hz), 8.09 (1H, dd, J=8 Hz, 1 Hz), 8.49 (1H,d, J=1 Hz)

REFERENCE EXAMPLE 137 2-(1-Naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.35 g (3.5 mmol) of 1-[(1-naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester obtained in Reference example 11 was dissolvedin 50 ml of methanol, 150 mg of 10% palladium-carbon was added thereto,and the mixture was stirred under a hydrogen atmosphere at roomtemperature overnight. After the reaction solution was filtered, thefiltrate was concentrated under reduced pressure. The obtained residuewas dissolved in 30 ml of methylene chloride, and 633 mg (3.3 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was addedthereto. After the mixture was stirred at room temperature for 4 hours,the reaction solution was concentrated under reduced pressure, ethylacetate was added thereto, and the mixture was successively washed withwater, a 10% aqueous potassium hydrogensulfate solution, a saturatedaqueous sodium hydrogencarbonate solution and saturated brine, followedby drying with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain 738 mg (88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.68 (3H, m), 1.70-2.00 (7H, m), 7.53-7.60 (2H,m), 7.67 (1H, td, 7 Hz, 1 Hz), 7.92 (1H, dd, J=7 Hz, 1 Hz), 8.03 (1H, d,J=7 Hz), 8.17 (1H, dd, J=7 Hz, 1 Hz), 9.33 (1H, dd, J=7 Hz, 1 Hz)

REFERENCE EXAMPLE 1382-[(RS)-2,3-Tetrahydrofuran-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

868 mg (3 mmol) of1-[[[(RS)-2,3-tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 686 mg(87%) of the title compound.

1H-NMR (CDCl₃, δ): 1.43-1.82 (10H, m), 3.56 (2H, d, J=9 Hz) 5.46 (½H, d,J=10 Hz), 5.48 (½H, d, J=10 Hz), 6.89 (1H, td, 8 Hz, 1 Hz), 6.93 (1H,dd, H=8 Hz, 1 Hz), 7.16 (1H, td, J=8 Hz, 1 Hz), 7.21 (1H, dd, J=8 Hz, 1Hz)

REFERENCE EXAMPLE 139 2-(2-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

53.2 g (224 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 49.8 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.57 (1H, m), 1.66-1.86 (9H, m), 6.58 (1H, dd,J=4 Hz, 2 Hz), 7.09 (1H, dd, J=4 Hz, 1 Hz), 7.65 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 140 2-(3-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.48 g (18.9 mmol) of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 4.02 g(97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.54-1.57 (1H, m), 1.63-1.86 (9H, m), 6.86 (1H, dd,J=2 Hz, 1 Hz), 7.51 (1H, t, J=2 Hz), 7.99 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1412-[2-(2-Furanyl)ethenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

10.0 g (38 mmol) of1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Reference example 132 to obtain 8.92 g (96%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.26-1.54 (2H, m), 1.66-1.84 (8H, m), 6.48 (1H, dd,J=2 Hz, 1 Hz), 6.53 (1H, d, J=16 Hz), 6.60 (1H, d, J=2 Hz), 7.22 (1H, d,J=16 Hz), 7.51 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 142 2-Cyclohexyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.15 g (16.3 mmol) of 1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 3.75 g(98%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.38 (3H, m), 1.44-1.56 (3H, m), 1.56-1.63 (3H,m), 1.63-1.84 (9H, m), 1.92-2.00 (2H, m), 2.43-2.49 (1H, m)

REFERENCE EXAMPLE 1432-(6-Benzothiazolyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

365 mg (1.2 mmol) of1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 287 mg (83%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.53-1.62 (4H, m), 1.68-1.79 (2H, m), 1.81-1.92 (4H,m), 8.19 (1H, dd, J=9 Hz, 2 Hz), 8.22 (1H, dd, J=9 Hz, 1 Hz), 8.65 (1H,dd, J=2 Hz, 1 Hz), 9.15 (1H, s)

REFERENCE EXAMPLE 144 2-(2-Thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

5.0 g (20 mmol) of 1-[(2-thienylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 4.46 g(96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.51-1.59 (1H, m), 1.61-1.69 (1H, m), 1.71-1.88 (8H,m), 7.14 (1H, dd, J=5 Hz, 4 Hz), 7.57 (1H, dd, J=5 Hz, 1 Hz), 7.70 (1H,dd J=4 Hz, 1 Hz)

REFERENCE EXAMPLE 145 2-(2-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to asolution of 10 g (42 mmol) of1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained inReference example 14 and 6.1 ml (44 mmol) of triethylamine intetrahydrofuran (80 ml), and the mixture was stirred at room temperaturefor 1 hour. The precipitated crystal was removed by filtration and thefiltrate was concentrated. The obtained crystal was washed with water togive 8.95 g (97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.57 (1H, m), 1.66-1.86 (9H, m), 6.58 (1H, dd,J=4 Hz, 2 Hz), 7.09 (1H, dd, J=4 Hz, 1 Hz), 7.65 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1462-(1,3-Benzodioxol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

5.8 g (20 mmol) of1-[[(1,3-benzodioxole)-5-carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 4.9 g (90%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.57 (1H, m), 1.63-1.75 (3H, m), 1.76-1.88 (6H,m), 6.05 (2H, s), 6.87 (1H, d, J=8 Hz), 7.46 (1H, d, J=2 Hz), 7.55 (1H,dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 1472-(2-Benzofuranyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

3.8 g (13 mmol) of1-[[(2-benzofuranyl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 3.4 g (96%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.74 (2H, m), 1.78-1.94 (8H, m), 7.33 (1H, ddd,J=8 Hz, 7 Hz, 1 Hz), 7.44 (1H, d, J=1 Hz), 7.46 (1H, ddd, J=8 Hz, 7 Hz,1 Hz), 7.63 (1H, ddd, J=8 Hz, 2 Hz, 1 Hz), 7.70 (1H, ddd, J=8 Hz, 2 Hz,1 Hz)

REFERENCE EXAMPLE 1482-(2-Pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

511 mg (2 mmol) of 1-[(2-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 405 mg(85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.54-1.77 (3H, m), 1.78-1.92 (7H, m), 7.62 (1H, ddd,J=7 Hz, 5 Hz, 2 Hz), 7.87 (1H, dt, J=7 Hz, 2 Hz), 8.04 (1H, dd, J=5 Hz,2 Hz), 8.82 (1H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 149 2-(3-Thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

253 mg (1 mmol) of 1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 234 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.52-1.87 (10H, m), 7.40 (1H, dd, J=5 Hz, 3 Hz), 7.60(1H, dd, J=5 Hz, 1 Hz), 8.00 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 1502-(3-Ethoxy-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

327 mg (1 mmol) of1-[[(3-ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 307 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.46 (3H, t, J=7 Hz), 1.49-1.84 (10H, m) 4.22 (2H, q,J=7 Hz), 6.86 (1H, d, J=6 Hz), 7.42 (1H, d, J=6 Hz)

REFERENCE EXAMPLE 1512-[2-[(S)-1-Phenylethyl]]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

275 mg (1 mmol) of1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 257 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.51-1.78 (13H, m), 3.89 (1H, q, J=7 Hz), 7.26-7.35(5H, m)

REFERENCE EXAMPLE 1522-(2-Pyrazinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1 mmol) of 1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 231 mg(quantitative) of the title compound.

1H-NMR (CDCl₃±6): 1.56-1.93 (10H, m), 8.78 (2H, m), 9.28 (1H, t, J=3 Hz)

REFERENCE EXAMPLE 1532-(5-Methylisoxazol-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1 g (7.87 mmol) of 5-methylisoxazole-4-carboxylic acid was added to 3 mlof thionyl chloride, and the mixture was stirred overnight. The reactionsolution was concentrated under reduced pressure, and the obtainedresidue was added to a solution of 1.13 g (7.87 mmol) of1-aminocyclohexanecarboxylic acid and 6.6 g (79 mmol) of sodiumhydrogencarbonate in 30 ml of toluene-30 ml of water. After the mixturewas stirred at room temperature overnight, the toluene layer wasseparated. The aqueous layer was neutralized by potassiumhydrogensulfate and extracted with ethyl acetate. After the obtainedorganic layer was washed with saturated brine, the layer was dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, methylene chloride was added thereto, and 332 mg (1.73 mmol)of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was addedthereto under ice-cooling. After the mixture was stirred at roomtemperature overnight, the reaction solution was concentrated underreduced pressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine, followed by drying with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain 295 mg (16%)of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.59 (1H, m), 1.64-1.72 (2H, m), 1.76-1.83 (7H,m), 2.75 (3H, s), 8.55 (1H, s)

REFERENCE EXAMPLE 154 2-cyclopentyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.98 g (15 mmol) of cyclopentanecarbonyl chloride was added to asolution of 2.16 g (15 mmol) of 1-aminocyclohexanecarboxylic acid and4.8 g (45 mmol) of sodium carbonate in 50 ml of ethyl acetate-50 ml ofwater under ice-cooling. After the mixture was stirred at roomtemperature overnight, ethyl acetate was added thereto, and the mixturewas washed with a 10% aqueous potassium hydrogensulfate solution, asaturated aqueous sodium bicarbonate solution, and then saturated brine.After the obtained organic layer was washed with saturated brine, thelayer was dried with anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, methylene chloride was added thereto, and1.59 g (8.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added thereto under ice-cooling. After the mixture wasstirred at room temperature overnight, the reaction solution wasconcentrated under reduced pressure, ethyl acetate was added thereto,and the mixture was successively washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain 1.41 g (42%) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.65 (5H, m), 1.67-1.76 (4H, m), 1.86-1.95 (8H,m), 2.80-2.89 (2H, m)

REFERENCE EXAMPLE 1552-(5-Methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

294 mg (1.1 mmol) of1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 273 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.62 (3H, m), 1.71-1.84 (7H, m), 2.55 (3H, s),6.79 (1H, d, J=3 Hz), 7.50 (1H, d, J=3 Hz)

REFERENCE EXAMPLE 1562-(4-Methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

305 mg (1.1 mmol) of1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 288 mg (90%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.60 (1H, m), 1.61-1.73 (3H, m), 1.76-1.90 (6H,m), 3.87 (3H, s), 6.96 (2H, dd, J=7 Hz, 2 Hz), 7.94 (2H, dd, J=7 Hz, 2Hz)

REFERENCE EXAMPLE 1572-(3-Methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1.1 mmol) of1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 249 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.60 (1H, m), 1.65-1.78 (3H, m), 1.78-1.90 (6H,m), 2.58 (3H, s), 6.95 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz)

REFERENCE EXAMPLE 1582-(3-Methyl-2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

902 mg (3.59 mmol) of1-[[(3-methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 233 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.48-1.61 (1H, m), 1.62-1.89 (9H, m), 2.36 (3H, s),6.40 (1H, d, J=1 Hz), 7.52 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 1592-(3-Pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

523 mg (2.11 mmol) of1-[(3-pyridinylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 486 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.90 (10H, m), 7.42 (1H, dd, J=8 Hz, 5 Hz), 8.27(1H, d, J=8 Hz), 8.78 (1H, d, J=5 Hz), 9.00 (1H, s)

REFERENCE EXAMPLE 1602-(1-Methyl-1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

187 mg (0.75 mmol) of1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Reference example 132 to obtain 172 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.44-1.85 (10H, m), 3.40 (3H, s), 6.18 (1H, dd, J=4Hz, 3 Hz), 6.82-6.86 (2H, m)

REFERENCE EXAMPLE 1612-[(R)-1-Phenylethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

303 mg (1.1 mmol) of1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 257 mg (90%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.45-1.65 (7H, m), 1.67-1.80 (6H, m), 3.89 (1H, q,J=7 Hz), 7.26-7.34 (5H, m)

REFERENCE EXAMPLE 1622-(1H-Indol-5-ylcarbonyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

329 mg (1.2 mmol) of1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 258 mg (80%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.56-1.89 (10H, m), 6.65 (1H, dd, J=3 Hz, 2 Hz),7.26-7.36 (1H, m), 7.46 (1H, d, J=9 Hz), 7.88 (1H, dd, J=9 Hz, 2 Hz),8.32 (1H, s), 8.35 (1H, br-s)

REFERENCE EXAMPLE 1632-(1-Cyclopentenylcarbonyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

237 mg (1 mmol) of1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 219 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.82 (10H, m), 1.99-2.10 (2H, m), 2.55-2.69 (2H,m), 2.69-2.80 (2H, m), 6.65-6.67 (1H, m)

REFERENCE EXAMPLE 1642-(4-Pyridinyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one

552 mg (2.2 mmol) of 1-[(4-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 450 mg(88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.92 (10H, m), 7.85 (2H, dd, J=5 Hz, 2 Hz), 8.80(2H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 1652-(1H-Pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

200 mg (0.85 mmol) of1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 184 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.51-1.65 (1H, m), 1.65-1.86 (9H, m), 6.32 (1H, dd,J=4 Hz, 2 Hz), 6.87 (1H, dd, J=4 Hz, 2 Hz), 7.01 (1H, dd, J=4 Hz, 2 Hz),9.37 (1H, br-s)

REFERENCE EXAMPLE 1662-(6-Hydroxy-2-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(6-hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 250 mg (97%) of thetitle compound.

1H-NMR (CDC₃, δ): 1.52 (1H, m), 1.78 (9H, m), 6.85-6.79 (2H, m), 7.50(1H, dd, J=9 Hz, 7 Hz)

REFERENCE EXAMPLE 1672-(2-Hydroxy-3-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(2-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 257 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.04-2.21 (10H, m), 6.40-6.50 (1H, m), 7.69-7.82 (1H,m), 8.28-8.35 (1H, m)

REFERENCE EXAMPLE 1682-(6-Hydroxy-3-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 257 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.45-1.86 (10H, m), 6.66 (1H, d, J=10 Hz), 8.02 (1H,d, J=2 Hz), 8.05 (1H, dd, J=10 Hz, 2 Hz)

REFERENCE EXAMPLE 1692-[2-(2-Furanyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.7 ml of 2N—NaOH aqueous solution was added to a solution of 478 mg(1.7 mmol) of 1-[[1-oxo-3-(2-furanyl)propyl]amino]cyclohexanecarboxylicacid methyl ester obtained in Reference example 64 in 2 ml oftetrahydrofuran, and the mixture was refluxed under heating for 3 hours.Ether was added to the reaction solution to wash it. After the separatedaqueous layer was neutralized by concentrated hydrochloric acid, thelayer was extracted with ethyl acetate. After the obtained organic layerwas washed with saturated brine, the layer was dried with anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. Then, 10 ml of methylene chloride and 377 mg (1.82 mmol) ofacid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrocloride wereadded to the residue, and the mixture was stirred at room temperatureovernight. The solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution, and then saturated brine, followed by dryingwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 198 mg (47%) of the title compound.

1H-NMR (CDCl₃, δ): 1.43-1.60 (4H, m), 1.60-1.80 (6H, m), 2.84 (2H, t,J=7 Hz), 3.05 (2H, t, J=7 Hz), 6.06 (1H, dd, J=2 Hz, 1 Hz), 6.27 (1H,dd, J=2 Hz, 1 Hz), 7.31 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1702-[1-[(2-Propoxy)carbonyl]piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

940 mg (2.76 mmol) of1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 818 mg(92%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24 (6H, d, J=6 Hz), 1.44-1.79 (12H, m), 1.90-1.98(2H, m), 2.62-2.69 (1H, m), 2.89-2.99 (2H, m), 4.03-4.19 (2H, m),4.88-4.97 (1H, m)

REFERENCE EXAMPLE 1712-[1-(Ethoxycarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

935 mg (2.86 mmol) of1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 730 mg(83%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.45-1.80 (12H, m), 1.92-1.99(2H, m), 2.62-2.70 (1H, m), 2.90-3.03 (2H, m), 4.03-4.20 (4H, m)

REFERENCE EXAMPLE 1722-[1-(2-Furanylcarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

196 mg (0.56 mmol) of1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 185 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.49-1.68 (5H, m), 1.68-1.80 (5H, m), 1.80-1.92 (2H,m), 2.03-2.10 (2H, m), 2.75-2.83 (1H, m), 3.05-3.31 (2H, m), 4.28-4.40(2H, m), 6.48 (1H, dd, J=3 Hz, 1 Hz), 7.00 (1H, dd, J=3 Hz, 1 Hz), 7.48(1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 1732-[[(2-Furanylcarbonyl)amino]methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1 mmol) of1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Reference example 132 to obtain 276 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.80 (10H, m), 4.45 (2H, d, J=6 Hz), 6.53 (1H,dd, J=3 Hz, 1 Hz), 6.90 (1H, br-s), 7.18 (1H, ddd, J=3 Hz, 2 Hz, 1 Hz),7.50 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1742-[(Benzoylamino)methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

724 mg (2.26 mmol) of1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Reference example 132 to obtain 631 mg (97%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.48-1.58 (1H, m), 1.63-1.80 (9H, m), 4.49 (2H, d,J=5 Hz), 6.76 (1H, br-s), 7.48 (2H, m), 7.55 (1H, m), 7.83 (2H, m)

REFERENCE EXAMPLE 1752-(4-Fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

After a suspension of 13.3 g (50 mmol) of1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid in 30 ml of aceticanhydride was stirred at 100° C. for 30 minutes, the reaction solutionwas concentrated under reduced pressure. Toluene was added to theresidue, and the mixture was washed with water, a saturated aqueoussodium hydrogencarbonate solution, and then saturated brine. After theorganic layer was dried with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 8.5 g (69%) of the title compound.

1H-NMR (CDCl₃, δ) 1.49-1.60 (1H, m), 1.63-1.90 (9H, m), 7.13-7.20 (2H,m), 8.00-8.05 (2H, m)

REFERENCE EXAMPLE 1762-[4-(4-Propylbdnzopiperazin-1-yl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.43 g (3.86 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Reference example 132 to obtain 1.33 g(98%) of the title compound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.50-1.61 (3H, m) 1.61-1.69(1H, m), 1.69-1.76 (2H, m), 1.79-1.84 (6H, m), 2.35 (1H, t, J=6 Hz),2.36 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.35 (4H, t, J=5 Hz), 6.91(2H, dd, J=2 Hz, 7 Hz), 7.86 (2H, dd, J=2 Hz, 7 Hz)

REFERENCE EXAMPLE 1772-[4-(4-Propylpiperazin-1-yl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onehydrochloride

After a suspension of 631 mg (1.54 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride in 18 ml of acetic anhydride was stirred at 100° C.for 1 hour, the reaction solution was concentrated under reducedpressure. The operation for adding toluene to the obtained residue anddistilling off it under reduced pressure was carried out three times,and acetic anhydride was removed by azeotropic distillation to obtain500 mg (83%) of the title compound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=8 Hz), 1.50-1.87 (10H, m), 1.95-2.06(2H, m), 2.86-3.01, (4H, m), 3.59-3.68 (2H, m), 3.79-3.90 (4H, m), 6.91(2H, dd, 2 Hz, 7 Hz), 7.91 (2H, dd, J=2 Hz, 7 Hz)

EXAMPLE 1N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

After 422 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 555 mg (2 mmol) of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, 322 mg(2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in20 ml of methylene chloride under ice-cooling, the mixture was stirredat room temperature for 18 hours. The reaction solution was concentratedunder reduced pressure, ethyl acetate was added to the residue, and themixture was washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution, andthen saturated brine. The organic layer was dried with anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 662mg (91%) of the title compound.

1H-NMR (CDCl₃, δ): 0.87 (3H, d, J=7 Hz), 0.92 (3H, d, J=7 Hz), 1.28-1.46(3H, m), 1.52-1.70 (3H, m), 1.73-1.82 (1H, m), 1.85-2.03 (4H, m), 2.76(1H, br-s), 3.42-4.47 (1H, m), 3.65-3.74 (2H, m), 5.02-5.16 (3H, m),6.36 (1H, d, J=8 Hz), 7.30-7.40 (5H, m)

EXAMPLE 2N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinol

234 mg (2 mmol) of L-norleucinol was used instead of L-valinol in theprocess according to Example 1 to obtain 350 mg (75%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 1.23-1.52 (9H, m), 1.58-1.70(3H, m), 1.83-2.04 (4H, m), 2.83 (1H, br-s), 3.34-3.40 (1H, m), 3.70(1H, br-s), 3.89 (1H, br-s), 5.02-5.13 (3H, m), 6.26 (1H, d, J=8 Hz),7.31-7.40 (5H, m)

EXAMPLE 3 N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

A solution of 8.81 ml (50.6 mmol) of N,N-diisopropylethylamine and 2.09g (20.2 mmol) of L-valinol in 10 ml of methylene chloride was added to asolution of 3.71 g (16.9 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 100 ml of toluene,and the mixture was refluxed under heating for 14 hours. The reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded to the residue, and the mixture was washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution, and then saturated brine. The organic layerwas dried with anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. Ethyl acetate was added to the residue, andthe mixture was stirred overnight. The obtained crystal was collected byfiltration to give 4.06 g (74.7%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz) 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 4 N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

Under an argon atmosphere, 72 mg (0.59 mmol) of isopropylchlorocarbonate was added to a solution of 200 mg (0.59 mmol) ofN-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine and 60 mg(0.59 mmol) of triethylamine in 2 ml of tetrahydrofuran underice-cooling. After the mixture was stirred at 0° C. for 2 hours, thereaction solution was filtered and poured into a solution of 45 mg (1.2mmol) of sodium borohydride in 1 ml of water, and the mixture wasstirred overnight. Ethyl acetate was added to the reaction solution, andthe mixture was successively washed with a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with sodium sulfate.After the solvent was distilled off under reduced pressure, the obtainedcrystal was washed with ether to give 30 mg (16%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz) 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 5 N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

Under an argon atmosphere, 31 mg (0.82 mmol) of lithium aluminum hydridewas added to 1 ml of diethyl ether placed in a flask. Under ice-cooling,a solution of 0.3 g (0.82 mmol) of the above compound in 1 ml oftetrahydrofuran was added to the flask, and the mixture was stirred for1 hour and 30 minutes. Ice water was added to the reaction solution.Ethyl acetate was added thereto, and the mixture was successively washedwith a 10% aqueous potassium hydrogensulfate solution, a saturatedaqueous sodium hydrogencarbonate solution and saturated brine. After itwas dried with sodium sulfate, the solvent was distilled off underreduced pressure. The obtained crystal was washed with ether to give 155mg (60%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz), 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 6N-[[1-[(4-Morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinol

513 mg (2 mmol) of 1-[(4-morpholinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid in theprocess according to Example 2 to obtain 215 mg (30%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.26-1.56 (9H, m) 1.60-1.73(3H, m), 1.85-2.05 (4H, m), 3.33-3.43 (5H, m), 3.54 (1H, t, J=7 Hz),3.66-3.73 (4H, m), 3.76-3.82 (1H, m), 3.83-3.93 (1H, m), 4.64 (1H,br-s), 6.35 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 178 N—[N—[(Phenylmethoxy)carbonyl]-L-leucyl]-L-valinol

N-[(Phenylmethoxy)carbonyl]-L-leucine was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 659 mg (94%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.83-0.99 (12H, m), 1.46-1.74 (3H, m), 1.78-1.90 (1H,m), 2.42 (1H, br-s), 3.57-3.72 (3H, m), 4.10-4.17 (1H, m), 5.04-5.17(3H, m), 6.22 (1H, d, J=7 Hz), 7.27-7.39 (5H, m)

REFERENCE EXAMPLE 179N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol

N-[(Phenylmethoxy)carbonyl]-L-leucine was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid andL-norleucinol was used instead of L-valinol in the process according toExample 1 to obtain 421 mg (58%) of the title compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 0.95 (6H, d, J=7 Hz), 1.23-2.72(9H, m), 2.44 (1H, br-s), 3.47-3.71 (2H, m), 3.89 (1H, br-s), 4.10-4.17(1H, m), 5.08-5.16 (3H, m), 6.10 (1H, d, J=6 Hz), 7.31-7.39 (5H, m)

REFERENCE EXAMPLE 180N—[N-(4-Morpholinylcarbonyl)-L-leucyl]-L-norleucinol

70 mg of 10% palladium-carbon was added to a solution of 700 mg (2mmol)of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol obtainedin Reference example 179 in 10 ml of methanol, and the mixture wasstirred under a hydrogen atmosphere at room temperature overnight. Afterthe reaction solution was filtered, the filtrate was concentrated underreduced pressure. 20 ml of methylene chloride and 404 mg (4 mmol) oftriethylamine were added to the residue. A solution of 299 mg (2 mmol)of 4-morpholinecarbonyl chloride in 3 ml of methylene chloride was addedto the mixture solution under ice-cooling. The reaction solution wasreturned to room temperature and stirred overnight. After the reactionsolution was washed with water and then saturated brine, it was driedwith anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Ether was added to the residue to wash it to obtain488 mg (71%) of the title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 0.94 (3H, d, J=7 Hz), 0.96 (3H,d, J=7 Hz), 1.23-1.37 (4H, m), 1.43-1.72 (5H, m), 2.67 (1H, br-s),3.31-3.44 (4H, m), 3.52-3.60 (1H, m), 3.65-3.73 (5H, m), 3.82-3.89 (1H,m), 4.24-4.32 (1H, m), 4.82 (1H, d, J=8 Hz), 6.31 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 181 N—[N-(2-Furanylcarbonyl)-L-leucyl]-L-valinol

30 mg of 10% palladium-carbon was added to a solution of 350 mg (1 mmol)of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinol obtained inReference example 178 in 10 ml of methanol, and the mixture was stirredunder a hydrogen atmosphere at room temperature overnight. After thereaction solution was filtered, the filtrate was concentrated underreduced pressure. 10 ml of ethyl acetate, 10 ml of water and further 159mg (1.5 mmol) of sodium carbonate were added to the residue. A solutionof 131 mg (1 mmol) of 2-furancarbonyl chloride in 3 ml of ethyl acetatewas added to the mixture solution under ice-cooling. The reactionsolution was returned to room temperature and stirred overnight. Theaqueous layer of reaction solution was separately collected andextracted with ethyl acetate. The organic layer was combined and afterit was washed with 10% potassium hydrogensulfate, and then saturatedbrine, it was dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, ether was added to the residue,and the crystal was washed to obtain 268 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz), 0.97 (3H,t, J=7 Hz), 0.99 (3H, t, J=7 Hz), 1.65-1.94 (4H, m), 2.47 (1H, t, J=5Hz), 3.63-3.74 (3H, m), 4.54-4.62 (1H, m), 6.42 (1H, d, J=7 Hz), 6.52(1H, dd, J=4 Hz, 2 Hz), 6.68 (1H, d, J=8 Hz), 7.14 (1H, dd, J=4 Hz, 1Hz), 7.47 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 182N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine ethylester

30 ml of dimethylformamide was added to a flask charged with 5 g (27mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one. Then, 3.53 g (27.4mmol) of diisopropylethylamine was added thereto, and the mixture wasstirred for 3 days. After the solvent was distilled off under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with a 10% aqueous potassium hydrogensulfatesolution and saturated brine, followed by drying with sodium sulfate.After the solvent was distilled off under reduced pressure, it waspurified by silica gel chromatography to obtain 8.3 g (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.25 (3H,t, J=7 Hz), 1.35-1.70 (6H, m), 1.98-2.01 (2H, m), 2.19-2.23 (2H, m),2.31-2.39 (1H, m), 4.11-4.19 (2H, m), 4.49 (1H, dd, J=9 Hz, 5 Hz), 6.34(1H, s), 6.53 (1H, dd, J=3 Hz, 1 Hz), 7.15 (1H, dd, J=3 Hz, 1 Hz), 7.48(1H, dd, J=2 Hz, 1 Hz), 7.58 (1H, d, J=9 Hz)

REFERENCE EXAMPLE 183N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine

10 ml of N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valineand 2.0 g (9.1 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture wasrefluxed under heating overnight. The reaction solution was distilledoff under reduced pressure, ethyl acetate was added thereto, and themixture was washed with a 10% aqueous potassium hydrogensulfate solutionand then saturated brine, followed by drying with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure and theresidue was purified by silica gel chromatography to obtain 384 mg(12.5%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.97 (3H, d, J=7 Hz) 1.33-1.48(3H, m), 1.64-1.73 (3H, m), 1.98 (2H, dt, J=14 Hz, 4 Hz), 2.22-2.30 (3H,m), 4.46 (1H, m), 6.43 (1H, s), 6.53 (1H, dd, J=3 Hz, 2 Hz), 7.17 (1H,dd, J=3 Hz, 1 Hz), 7.48 (1H, dd, J=2 Hz, 1 Hz), 7.55 (1H, d, J=8 Hz)

EXAMPLE 7N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

Under an argon atmosphere, 1.22 g (9.44 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 1.50 g(9.44 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, the mixture was stirred for 15 minutes. Further, a solutionof 570 mg (1.57 mmol) ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol in3 ml of anhydrous dimethyl sulfoxide was added to the reaction solutionunder ice-cooling, and the mixture was stirred at the same temperaturefor 2 hours. The reaction solution was poured into ice water andextracted with ethyl acetate twice. The organic layer was washed with a10% aqueous citric acid solution, a saturated aqueous sodiumhydrogencarbonate solution, and then saturated brine, and after it wasdried with anhydrous magnesium sulfate, the solvent was distilled offunder reduced pressure. 20 ml of diisopropyl ether was added to theresidue, and the mixture was stirred at room temperature for 18 hours.The obtained crystal was collected by filtration to give 435 mg (77%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, d, J=7 Hz), 0.97 (3H, d, J=7 Hz) 1.22-1.44(3H, m), 1.59-1.70 (3H, m), 1.85-2.15 (4H, m), 2.22-2.34 (1H, m), 4.48(1H, s), 4.96 (1H, s), 5.11 (2H, s), 7.10-7.41 (6H, m), 9.59 (1H, s)

EXAMPLE 8N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinal

465 mg of (1.24 mmol) ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 350 mg (75%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.88 (3H, d, J=7 Hz), 1.19-1.43 (7H, m), 1.51-1.70(4H, m), 1.82-2.13 (5H, m), 4.42 (1H, br-s), 4.95 (1H, s), 5.10 (2H, s),7.10 (1H, br-s), 7.29-7.42 (5H, m), 9.53 (1H, s)

EXAMPLE 9 N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal

3.50 g (10.9 mmol) ofN-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol was usedinstead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 3.14 g (90.3%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.94 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz) 1.30-1.40(1H, m), 1.41-1.54 (2H, m), 1.62-1.76 (3H, m), 1.95-2.04 (2H, m),2.20-2.26 (1H, m), 2.28-2.36 (2H, m), 4.44 (1H, dd, J=8 Hz, 5 Hz,), 6.38(1H, br-s), 6.54 (1H, dd, J=4 Hz, 2 Hz), 7.15 (1H, dd, J=4 Hz, 1 Hz),7.49 (1H, dd, J=2 Hz, 1 Hz), 7.68 (1H, d, J=8 Hz), 9.60 (1H, s)

EXAMPLE 10N-[[1-[(4-Morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinal

205 mg (0.58 mmol) ofN-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 125 mg (61%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.23-1.42 (7H, m), 1.52-1.71(4H, m), 1.83-1.98 (3H, m), 2.05-2.18 (2H, m), 3.34-3.42 (4H, m),3.65-3.76 (4H, m), 4.37 (1H, dt, J=7 Hz, 7 Hz), 4.48 (1H, s), 7.81 (1H,d, J=7 Hz), 9.55 (1H, s)

REFERENCE EXAMPLE 184 N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-valinal

280 mg (0.8 mmol) of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 278 mg (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.83-1.01 (12H, m), 1.48-1.59 (1H, m), 1.62-1.74 (2H,m), 2.28-2.37 (1H, m), 4.19-4.28 (1H, m), 4.51-4.56 (1H, m), 5.05-5.17(3H, m), 6.51 (1H, d, J=7 Hz), 7.27-7.39 (5H, m), 9.64 (1H, s)

REFERENCE EXAMPLE 185N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinal

253 mg (0.7 mmol) ofN—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol was used insteadof N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolin the process according to Example 7 to obtain 195 mg (78%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 0.95 (6H, d, J=7 Hz) 1.22-1.39(4H, m), 1.47-1.72 (4H, m), 1.83-1.97 (1H, m), 4.19-4.26 (1H, m),4.45-4.53 (1H, m), 5.08-5.17 (3H, m), 6.46 (1H, br-s), 7.29-7.39 (5H,m), 9.57 (1H, s)

REFERENCE EXAMPLE 186N—[N-(4-Morpholinylcarbonyl)-L-leucyl]-L-norleucinal

473 mg (1.4 mmol) ofN—[N-(4-morpholinylcarbonyl)-L-leucyl]-L-norleucinol was used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 315 mg (67%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 0.96 (3H, d, J=6 Hz), 0.97 (3H,d, J=6 Hz), 1.23-1.39 (4H, m), 1.50-1.76 (4H, m), 1.85-1.96 (1H, m),3.32-3.43 (4H, m), 3.63-3.72 (4H, m), 4.37-4.46 (2H, m), 4.86 (1H, d,J=8 Hz), 6.69 (1H, d, J=7 Hz), 9.56 (1H, s)

REFERENCE EXAMPLE 187 N—[N-(2-Furanylcarbonyl)-L-leucyl]-L-valinal

256 mg (0.8 mmol) of N—[N-(2-furanylcarbonyl)-L-leucyl]-L-valinol wasused instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Example 7 to obtain 175 mg (72%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.90-1.02 (12H, m), 1.64-1.82 (3H, m), 2.29-2.36 (1H,m), 4.52 (1H, dd, J=8 Hz, 5 Hz), 4.67 (1H, td, J=8 Hz, 6 Hz), 6.51 (1H,dd, J=4 Hz, 2 Hz), 6.67-6.73 (2H, m), 7.14 (1H, dd, J=4 Hz, 1 Hz), 7.46(1H, dd, J=2 Hz, 1 Hz), 9.65 (1H, s)

REFERENCE EXAMPLE 1881-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

Under ice-cooling, 5.9 g (31 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g(28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylenechloride. Afterthe mixture was stirred at room temperature overnight, the reactionsolvent was distilled off under reduced pressure. Water was added to theresidue and the mixture was extracted with ethyl acetate twice. Theobtained organic layer was washed with a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution, and then saturated brine, followed by drying with anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and diethyl ether was added to the obtained residue, followed bystirring of the mixture overnight. The crystal was collected byfiltration and was heated and dried under reduced pressure to obtain 10g (91%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m), 2.12-2.25 (2H,m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m),7.77 (1H, s), 7.80-7.91 (2H, m)

REFERENCE EXAMPLE 1891-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid

42 ml of 2N sodium hydroxide aqueous solution was added to a solution of10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture wasrefluxed under heating for 3 days. After ether was added to the reactionsolution to wash it, the aqueous layer was neutralized by concentratedhydrochloric acid, and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure togive 6.1 g (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.85 (6H, m), 1.91-2.08 (2H, m), 2.21-2.35 (2H,m), 6.22 (1H, s), 7.38-7.53 (2H, m), 7.80-7.93 (3H, m)

REFERENCE EXAMPLE 1902-(2-Benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.1 g (21 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 5 g (16 mmol) of1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid in 50 ml ofmethylene chloride. After the mixture was stirred at room temperaturefor 4 hours, the reaction solution was concentrated under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine. The organic layer was dried with anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure toobtain 3.5 g (75%) of the title compound.

1H-NMR (CDCl₃, δ): 1.45-1.98 (10H, m), 7.38-7.51 (2H, m), 7.80-7.91 (2H,m), 7.93 (1H, s)

REFERENCE EXAMPLE 1911-[[[4-(Chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

Under ice-cooling, 9.96 g (52 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 8.8 g (52 mmol) of 4-(chloromethyl)benzoic acid, 10 g (52mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride,15 g (152 mmol) of triethylamine and 8.63 g (56 mmol) of1-hydroxybenzotriazole in methylene chloride. After the mixture wasstirred at room temperature overnight, the reaction solvent wasdistilled off under reduced pressure. Water was added to the residue andthe mixture was extracted with ethyl acetate twice. The obtained organiclayer was washed with a 10% aqueous potassium hydrogensulfate solution,a saturated aqueous sodium hydrogencarbonate solution, and thensaturated brine, followed by drying with anhydrous sodium sulfate. Theobtained residue was purified by silica gel column chromatography togive 8.5 g (53%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.73 (6H, m), 1.83-2.00 (2H, m), 2.08-2.21 (2H,m), 3.71 (3H, s), 5.56 (2H, s), 6.30 (1H, s), 7.44 (2H, dd, J=8 Hz, 2Hz), 7.75 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 1921-[[[4-(Hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

Under ice-cooling, 6.94 g (36 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g(35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After themixture was stirred at room temperature overnight, the reaction solventwas distilled off under reduced pressure. Water was added to the residueand the mixture was extracted with ethyl acetate twice. The obtainedorganic layer was washed with a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution, andthen saturated brine, followed by drying with anhydrous sodium sulfate.The obtained residue was purified by silica gel column chromatography togive 6.83 g (56%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m), 4.73 (2H, m),5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m),7.62-7.79 (2H, m)

REFERENCE EXAMPLE 1931-[[[4-[(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

30 ml of 40% aqueous dimethylamine solution was added to 4.5 g (14.5mmol) of1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester, and the mixture was refluxed under heating for 3 hours.The reaction solution was distilled off under reduced pressure, asaturated aqueous sodium bicarbonate solution was added thereto, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, diisopropyl ether wasadded to the residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration to obtain 2.3 g (50%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.30-2.19 (10H, m), 2.24 (6H, s), 3.46 (2H, s), 3.76(3H, s), 6.22 (1H, s), 7.38 (2H, d, J=9 Hz), 7.73 (2H, d, J=9 Hz)

REFERENCE EXAMPLE 1941-[[[4-[(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 1 g (9 mmol) of methanesulfonyl chloride was addeddropwise to a solution of 3 g (8 mmol) of1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 2.46 g (24 mmol) of triethylamine in methylenechloride. After the reaction mixture was stirred at room temperature for1 hour, 20 ml of 2N dimethylamine-tetrahydrofuran solution was added,and the mixture was stirred overnight. The reaction solution wasdistilled off under reduced pressure, a saturated aqueous sodiumbicarbonate solution was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure and it was purified by silica gel columnchromatography to obtain 700 mg (22%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-2.01 (9H, m), 2.12-2.28 (1H, m), 2.24 (6H, s),3.46 (2H, s), 5.17 (2H, s), 6.25 (1H, s), 7.21-7.32 (5H, m), 7.37 (2H,dd, J=9 Hz, 2 Hz), 7.10 (2H, dd, J=9 Hz, 2 Hz)

REFERENCE EXAMPLE 1952-[4-[(Dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

29 ml of 2N aqueous sodium hydroxide solution was added to a solution of1.85 g (5.8 mmol) of1-[[[4-[(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 29 ml of tetrahydrofuran, and the mixture wasrefluxed under heating overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction mixture was distilled offunder reduced pressure. 30 ml of methylene chloride, 1.76 g (17 mmol) oftriethylamine and 1.67 g (8.7 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 1.33 g (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.88 (10H, m), 2.25 (6H, s), 3.48 (2H, s), 7.43(2H, dd, J=9 Hz, 2 Hz), 7.96 (2H, dd, J=9 Hz, 2 Hz)

REFERENCE EXAMPLE 1962-[4-[(Dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

0.7 ml of 2N aqueous sodium hydroxide solution was added to a solutionof 100 mg (0.25 mmol) of1-[[[4-[(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 1 ml of tetrahydrofuran, and the mixture wasrefluxed under heating overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction mixture was distilled offunder reduced pressure. 3 ml of methylene chloride, 126 mg (1.25 mmol)of triethylamine and 96 mg (0.5 mmol)1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, the mixture was stirred for 1 hour. The reaction mixturewas distilled off under reduced pressure, an aqueous sodium bicarbonatesolution was added thereto, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumbicarbonate solution and dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain 52 mg (68%)of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.88 (10H, m), 2.25 (6H, s), 3.48 (2H, s), 7.43(2H, dd, J=9 Hz, 2 Hz), 7.96 (2H, dd, J=9 Hz, 2 Hz)

REFERENCE EXAMPLE 1971-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 628 mg (5.5 mmol) of methanesulfonyl chloride wasadded dropwise to a solution of 1.83 g (5 mmol) of1-[[[4-(hydroxymethylphenyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 1.52 g (15 mmol) of triethylamine in methylenechloride. After the mixture was stirred at room temperature for 1 hour,5 ml of morpholine was added thereto, and the mixture was stirredovernight. The reaction mixture was distilled off under reducedpressure, a saturated aqueous sodium bicarbonate solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure and it waspurified by silica gel column chromatography to obtain 1 g (57%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.25-1.79 (6H, m), 1.89-2.03 (2H, m), 2.15-2.29 (2H,m), 2.43 (4H, t, J=5 Hz), 3.53 (2H, s), 3.70 (4H, t, J=5 Hz), 5.17 (2H,s), 6.21 (1H, s), 7.21-7.38 (5H, m), 7.39 (2H, d, J=8 Hz), 7.71 (2H, d,J=8 Hz)

REFERENCE EXAMPLE 1981-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

30 ml of morpholine was added to 4 g (13 mmol) of1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester, and the mixture was refluxed under heating for 1 hour. Thereaction solution was distilled off under reduced pressure, a saturatedaqueous sodium bicarbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, diethyl ether was added to theresidue, and the mixture was stirred overnight. The precipitated solidwas collected by filtration to obtain 3.8 g (83%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.80 (6H, m), 1.80-1.99 (2H, m), 2.11-2.21 (2H,m), 2.38-2.49 (4H, m), 3.54 (2H, s), 3.63-3.74 (4H, m), 3.73 (3H, s),6.22 (1H, s), 7.41 (2H, d, J=8 Hz), 7.73 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1992-[4-(4-Morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

18 ml of 2N sodium hydroxide aqueous solution was added to a solution of2.07 g (5.7 mmol) of1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 18 ml of tetrahydrofuran, and the mixture wasrefluxed under heating overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction solution was distilled offunder reduced pressure. 30 ml of methylene chloride, 1.74 g (17 mmol) oftriethylamine and 1.65 g (8.6 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 1.27 g (60%) of the title compound.

1H-NMR (CDCl₃, δ): 1.42-1.80 (10H, m), 2.44 (4H, t, J=5 Hz) 3.56 (2H,s), 3.71 (4H, t, J=5 Hz), 7.45 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 2002-[4-(4-Morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

2 ml of 2N aqueous sodium hydroxide solution was added to a solution of300 mg (0.69 mmol) of1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 2 ml of tetrahydrofuran, and the mixture wasrefluxed under heating overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction solution was distilled offunder reduced pressure. 3 ml of methylene chloride, 698 mg (6.9 mmol) oftriethylamine and 264 mg (1.38 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionmixture was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 191 mg (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.42-1.80 (10H, m), 2.44 (4H, t, J=5 Hz), 3.56 (2H,s), 3.71 (4H, t, J=5 Hz), 7.45 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 2011-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 5.29 g (374 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 8.84 g (23.0 mmol) of4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide,4.19 g (27.6 mmol) of 1-hydroxybenzotriazole, 6.44 g (27.6 mmol) of1-aminocyclohexanecarboxylic acid phenylmethyl ester and 11.9 g (92mmol) of N,N-diisopropylethylamine in 120 ml of dimethylformamide. Afterthe mixture was stirred at room temperature overnight, the reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded thereto, and the mixture was successively washed with water, asaturated aqueous sodium hydrogencarbonate solution and saturated brine,followed by drying with anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, ether was added to the residue anda crystal was washed to obtain 11.8 g (quantitative) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (1H, m), 1.45-1.61 (2H, m), 1.62-1.75 (3H,m), 1.91-2.01 (2H, m), 2.18-2.24 (2H, m), 2.37 (3H, s), 2.56 (4H, t, J=5Hz), 3.59 (4H, t, J=5 Hz), 5.18 (2H, s), 6.23 (1H, br-s), 6.88 (1H, s),7.25-7.34 (5H, m), 7.76 (2H, dd, J=8 Hz, 2 Hz), 7.90 (2H, dd, J=8 Hz, 2Hz)

REFERENCE EXAMPLE 2021-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid

35 ml of 2N sodium hydroxide aqueous solution was added to a solution of11.8 g (23.0 mmol) of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 120 ml of tetrahydrofuran, and the mixturewas refluxed under heating for 15 hours. Ether was added to the reactionmixture, and the aqueous layer was separated. Concentrated hydrochloricacid was added to the separated aqueous layer to neutralize it and theprecipitated crystal was collected by filtration to obtain 6.60 g (67%)of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.38 (1H, m), 1.40-1.51 (2H, m), 1.58-1.73 (3H,m), 1.85-2.00 (2H, m), 2.10-2.21 (2H, m), 2.47 (3H, s), 2.66-2.75 (4H,m), 3.54-4.04 (4H, m), 6.38 (1H, br-s), 6.83 (1H, s), 7.69 (2H, d, J=8Hz), 7.76 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 2032-[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

450 mg (2.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 910 mg (2.1 mmol) of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid in 20 ml of dimethylformamide. After the mixture was stirred atroom temperature for 4 hours, the reaction solution was concentratedunder reduced pressure, ethyl acetate was added thereto, and the mixturewas successively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain 577 mg (67%) of the title compound.

1H-NMR (CDCl₃, δ): 1.51-1.62 (1H, m), 1.62-1.71 (1H, m), 1.71-1.78 (2H,m), 1.78-1.90 (6H, m), 2.37 (3H, s), 2.56 (4H, t, J=5 Hz), 3.60 (4H, t,J=5 Hz), 6.92 (1H, s), 7.94 (2H, d, J=8 Hz), 8.00 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 2044-[[2-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acidhydrobromide

After a solution of 2.47 g (16.9 mmol) of4-(4-morpholinyl)piperidine-1-thiocarboxamide and 4.08 g (16.9 mmol) of4-(bromoacetyl)benzoic acid in 150 ml of ethanol was refluxed underheating for 2 hours, the mixture was cooled to room temperature. After150 ml of ether was added to the reaction solution and the mixture wasstirred at 4° C. overnight, the precipitated crystal was collected byfiltration to obtain 4.64 g (95%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.68-1.80 (2H, m), 2.17-2.25 (2H, m), 3.07-3.20(4H, m), 3.21-3.63 (5H, m), 3.64-3.78 (1H, m), 3.98-4.10 (1H, m),4.10-4.18 (2H, m), 7.51 (1H, s), 7.95-7.99 (4H, m)

REFERENCE EXAMPLE 2051-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

4.50 g (9.90 mmol) of4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acidhydrobromide was used instead of4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide and1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference example 201 to obtain 5.08 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.45-1.74 (7H, m), 1.93-2.01 (4H,m), 2.14-2.21 (2H, m), 2.41-2.50 (1H, m), 2.58 (4H, t, J=5 Hz), 3.07(2H, dd, J=13 Hz, 13 Hz), 3.73 (4H, t, J=5 Hz), 3.74 (3H, s), 4.13 (2H,d, J=13 Hz), 6.25 (1H, br-s), 6.86 (1H, s), 7.78 (2H, dd, J=8 Hz, 2 Hz),7.90 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 2061-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid

5.08 g (9.90 mmol) of1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in the process according to Reference example202 to obtain 4.93 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.45 (1H, m), 1.46-1.60 (2H, m), 1.61-1.77 (5H,m), 1.90-2.03 (4H, m), 2.15-2.25 (2H, m), 2.44-2.52 (1H, m), 2.62 (4H,t, J=5 Hz), 3.08 (2H, dd, J=13 Hz, 13 Hz), 3.78 (4H, t, J=5 Hz), 4.14(2H, d, J=13 Hz), 6.70 (1H, br-s), 6.88 (1H, s), 7.79 (2H, d, J=8 Hz),7.90 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 2072-[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.93 g (9.90 mmol) of1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid in the process according to Reference example 203 to obtain 3.00 g(63%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.61 (1H, m), 1.61-1.71 (3H, m), 1.71-1.79 (2H,m), 1.79-1.89 (5H, m), 1.91-2.00 (2H, m), 2.40-2.48 (1H, m), 2.59 (4H,t, J=5 Hz), 3.09 (2H, d, J=12 Hz), 3.74 (4H, t, J=5 Hz), 4.13 (2H, d,J=12 Hz), 6.90 (1H, s), 7.96 (2H, dd, J=7 Hz, 2 Hz), 8.00 (2H, dd, J=7Hz, 2 Hz)

EXAMPLE 11N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinol

288 mg (2 mmol) of L-phenylglycinol was added to a solution of 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-on in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added to the mixture and the precipitated crystal wascollected by filtration. The obtained crystal was dried under reducedpressure to give 730 mg (98%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.80 (6H, m), 1.91-2.12 (2H, m), 2.19-2.38 (2H,m), 2.91 (1H, br-s), 3.73-3.83 (1H, m), 3.89-4.02 (1H, m), 5.07-5.20(1H, m), 6.26 (1H, s), 7.20-7.49 (8H, m), 7.83 (1H, s), 7.84-7.92 (2H,m)

EXAMPLE 12N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under ice-cooling, 585 mg (1.38 mmol) of Des Martin periodinane wasadded to a solution of 100 mg (0.23 mmol) ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added thereto. Sodiumthiosulfate was added thereto until the solution became transparent, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium bicarbonate solution andsaturated brine and dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, ethyl acetate was added to theobtained residue, and the mixture was stirred for 1 hour. Theprecipitated solid was collected by filtration to obtain 55 mg (57%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.21-1.80 (6H, m), 1.83-2.18 (2H, m), 2.23-2.40 (2H,m), 5.51 (1H, d, J=5 Hz), 6.10 (1H, s), 7.21-7.52 (7H, m), 7.83 (1H, s),7.84-7.96 (2H, m), 8.18 (1H, d, J=5 Hz), 9.55 (1H, s)

EXAMPLE 13N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninol

284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added to the mixture and the precipitated crystal wascollected by filtration. The obtained crystal was dried under reducedpressure to give 722 mg (98%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-2.29 (16H, m), 2.45-2.63 (1H, m), 3.06 (1H,br-s), 3.45-3.61 (1H, m), 3.73-3.82 (1H, m), 3.97-4.05 (1H, m), 6.29(1H, s), 6.85 (1H, br-s), 7.38-7.50 (2H, m), 7.82 (1H, s), 7.83-7.90(2H, m)

EXAMPLE 14N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninal

Under an argon gas atmosphere, 245 mg (1.9 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 297 mg(1.9 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, the mixture was stirred for 15 minutes. Further, underice-cooling, 100 mg (0.23 mmol) ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolwas added to the reaction solution, and the mixture was stirred at thesame temperature for 2 hours. The reaction solution was poured intoice-water, and the mixture was extracted with ethyl acetate twice. Afterthe organic layer was washed with a 10% aqueous citric acid solution, asaturated aqueous sodium hydrogencarbonate solution and then saturatedbrine and dried with anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. 20 ml of diisopropyl ether wasadded to the residue, and the mixture was stirred at room temperaturefor 18 hours. The obtained crystal was collected by filtration toquantitatively give the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.80 (9H, m), 1.91-2.09 (5H, m), 2.20-2.35 (2H,m), 2.50-2.63 (1H, m), 4.43-4.59 (1H, m), 6.19 (1H, s), 7.38-7.52 (2H,m), 7.67 (1H, d, J=7 Hz), 7.71 (1H, s), 7.80-7.89 (2H, m), 9.61 (1H, s)

EXAMPLE 15N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

44 mg (0.32 mmol) of L-phenylglycinol was added to a solution of 100 mg(0.29 mmol) of2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure togive 46 mg (34%) of the title compound.

1H-NMR (CDCl₃, δ) 1.25-1.80 (6H, m), 1.92-2.10 (2H, m), 2.18-2.32 (2H,m), 2.37-2.50 (4H, m), 2.99 (1H, br-s), 3.55 (2H, s), 3.62-3.71 (4H, m),3.71-3.83 (1H, m), 3.91-4.02 (1H, m), 5.05-5.18 (1H, m), 6.24 (1H, s),7.17-7.37 (6H, m), 7.44 (2H, d, J=8 Hz), 7.73 (2H, d, J=8 Hz)

EXAMPLE 16N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under ice-cooling, 254 mg (0.6 mmol) of Des Martin periodinane was addedto a solution of 46 mg (0.1 mmol) ofN-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added to the reaction mixture.Sodium thiosulfate was added thereto until the solution becametransparent, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and saturated brine and dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, ethyl acetate wasadded to the obtained residue, and the mixture was stirred for 1 hour.The precipitated solid was collected by filtration to obtain 30 mg (60%)of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.37 (10H, m), 2.37-2.60 (4H, m), 3.55 (2H, s),3.61-3.80 (4H, m), 5.49 (1H, d, J=6 Hz), 6.16 (1H, s), 7.20-7.58 (7H,m), 7.75 (2H, d, J=8 Hz), 8.27 (1H, d, J=6 Hz), 9.54 (1H, s)

EXAMPLE 17N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

43 mg (0.32 mmol) of L-methioninol was added to a solution of 100 mg(0.29 mmol) of2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added thereto and the precipitated crystal wascollected by filtration. The obtained crystal was dried under reducedpressure to give 65 mg (49%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-2.23 (15H, m), 2.35-2.45 (4H, m), 2.45-2.62 (2H,m), 3.12 (1H, br-s), 3.40-3.60 (3H, m), 3.60-3.82 (5H, m), 3.95-4.05(1H, m), 6.28 (1H, s), 6.80 (1H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 7.72(2H, d, J=8 Hz)

EXAMPLE 18N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

Under ice-cooling, 356 mg (0.84 mmol) of Des Martin periodinane wasadded to a solution of 65 mg (0.14 mmol) ofN-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added to the reaction solution.Sodium thiosulfate was added thereto until the solution becametransparent, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and saturated brine and dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to obtain 55 mg(85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.80 (21H, m), 3.56 (2H, s), 3.60-3.81 (4H, m),4.40-4.58 (1H, m), 5.12 (1H, d, J=7 Hz), 6.18 (1H, s), 7.44 (2H, d, J=8Hz), 7.73 (2H, d, J=8 Hz), 9.59 (1H, s)

EXAMPLE 19N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

100 mg (0.74 mmol) of L-methioninol was added to a solution of 250 mg(0.68 mmol) of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 20 ml of dimethylformamide. After the mixture was stirred at 80° C.for 15 hours, the reaction solution was concentrated under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diisopropyl ether was added to the residue. Thecrystal was washed to obtain 319 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.61 (3H, m), 1.65-1.80 (3H, m), 1.80-1.86 (2H,m), 1.96-2.05 (2H, m), 2.07 (3H, s), 2.15-2.29 (2H, m), 2.37 (3H, s),2.51-2.60 (2H, m), 2.56 (4H, t, J=5 Hz), 3.14-3.21 (1H, m), 3.50-3.56(1H, m), 3.59 (4H, t, J=5 Hz), 3.77-3.84 (1H, m), 4.00-4.06 (1H, m),6.30 (1H, br-s), 6.85 (1H, d, J=7 Hz), 6.90 (1H, s), 7.76 (2H, dd, J=8Hz, 2 Hz), 7.92 (2H, dd, J=8 Hz, 2 Hz)

EXAMPLE 20N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

Under an argon gas atmosphere, 453 mg (3.5 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 658 mg(3.5 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, a solution of 319 mg (0.58 mmol) ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin 3 ml of anhydrous dimethyl sulfoxide was added to the reactionsolution, and the mixture was stirred at the same temperature for 2hours. The reaction solution was poured into ice-water, and the mixturewas extracted with ethyl acetate twice. The organic layer was washedwith a saturated aqueous sodium hydrogencarbonate solution and thensaturated brine and dried with anhydrous magnesium sulfate. Thereafter,the solvent was distilled off under reduced pressure. 20 ml ofdiisopropyl ether was added to the residue, and the mixture was stirredat room temperature for 18 hours. The obtained crystal was collected byfiltration to give 203 mg (64%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.78 (6H, m), 1.98-2.08 (3H, m), 2.02 (3H, s),2.21-2.57 (3H, m), 2.38 (3H, s), 2.55 (4H, t, J=5 Hz), 2.56 (2H, m),3.61 (4H, t, J=5 Hz), 4.49 (1H, dt, J=8 Hz, 5 Hz), 6.17 (1H, br-s), 6.90(1H, s), 7.78 (2H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 7.92 (2H, d, J=8Hz), 9.62 (1H, s)

EXAMPLE 21N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

96 mg (0.7 mmol) of L-phenylglycinol was used instead of L-methioninolin the process according to Example 19 to obtain 220 mg (57%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.34-1.43 (1H, m), 1.42-1.61 (2H, m), 1.61-1.79 (3H,m), 1.96-2.10 (2H, m), 2.20-2.29 (1H, m), 2.30-2.36 (1H, m), 2.37 (3H,s), 2.56 (4H, t, J=5 Hz), 3.01-3.08 (1H, m), 3.60 (4H, t, J=5 Hz),3.76-3.85 (1H, m), 3.92-4.01 (1H, m), 5.09-5.15 (1H, m), 6.27 (1H,br-s), 6.90 (1H, s), 7.24-7.30 (3H, m), 7.31-7.36 (2H, m), 7.37 (1H, d,J=7 Hz), 7.78 (2H, d, J=8 Hz) 7.92 (2H, d, J=8 Hz)

EXAMPLE 22N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under an argon gas atmosphere, 310 mg (2.4 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 382 mg(2.4 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, a solution of 220 mg (0.4 mmol) ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolin 3 ml of anhydrous dimethyl sulfoxide was added to the reactionsolution, and the mixture was stirred at the same temperature for 30minutes. After the reaction, under ice-cooling, 200 ml of water wasadded to the reaction solution, and thereafter the mixture was stirredat room temperature for 3 hours. The precipitated crystal was washedwith diethyl ether again to obtain 67 mg (31%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.82 (6H, m), 2.25-2.39 (2H, m), 2.50-2.59 (1H,m), 2.62 (3H, s), 2.75 (4H, t, J=5 Hz), 3.06-3.15 (1H, m), 3.72 (4H, t,J=5 Hz), 5.51 (1H, d, J=6 Hz), 6.16 (1H, br-s), 6.91 (1H, s), 7.21-7.38(5H, m), 7.38 (1H, d, J=6 Hz), 7.79 (2H, d, J=8 Hz), 7.92 (2H, d, J=8Hz), 9.56 (1H, s)

EXAMPLE 23N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein the process according to Example 19 to obtain 501 mg (81%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.35-1.80 (7H, m), 1.81-1.89 (2H, m), 1.92-2.09 (4H,m), 2.07 (3H, s), 2.15-2.23 (3H, m), 2.41-2.49 (1H, m), 2.54 (2H, t, J=6Hz), 2.57 (4H, t, J=5 Hz), 3.08 (2H, dd, J=13 Hz, 13 Hz), 3.18 (1H, t,J=7 Hz), 3.50-3.58 (1H, m), 3.74 (4H, t, J=5 Hz), 3.77-3.85 (1H, m),4.00-4.08 (1H, m), 4.12 (2H, d, J=13 Hz), 6.30 (1H, br-s), 6.83 (1H, d,J=8 Hz), 6.88 (1H, s), 7.77 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

EXAMPLE 24N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

501 mg (0.81 mmol) ofN-[[1-[[[4-[2-[(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolwas used instead ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 20 to obtain 100 mg (20%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.36-1.56 (3H, m), 1.61-1.79 (6H, m), 1.93-2.07 (5H,m), 2.02 (3H, s), 2.04-2.15 (2H, m), 2.40 (2.49 (1H, m), 2.45 (2H, t,J=6 Hz), 2.58 (4H, t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.74 (4H,t, J=5 Hz), 4.12 (2H, d, J=12 Hz), 4.49 (1H, dd, J=8 Hz, 5 Hz,), 6.15(1H, br-s), 6.88 (1H, s), 7.78 (2H, d J=8 Hz), 7.85 (1H, d, J=8 Hz),7.93 (2H, d, J=8 Hz), 9.62 (1H, s)

EXAMPLE 25N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 137 mg (1.00 mmol) of L-phenylglycinol was used instead ofL-methioninol in the process according to Example 19 to obtain 324 mg(52%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.78 (9H, m), 1.95-2.11 (4H, m), 2.20-2.27 (1H,m), 2.29-2.36 (1H, m), 2.40-2.49 (1H, m) 2.59 (4H, t, J=5 Hz), 3.09 (2H,dd, J=13 Hz, 13 Hz), 3.74 (4H, t, J=5 Hz), 3.78-3.82 (1H, m), 3.96-4.00(1H, m), 4.12 (2H, d, J=13 Hz), 5.09-5.14 (1H, m), 6.28 (1H, br-s), 6.88(1H, s), 7.25-7.30 (1H, m) 7.30-7.35 (4H, m), 7.78 (1H, d, J=8 Hz), 7.78(2H, dd, J=7 Hz, 2 Hz), 7.92 (2H, dd, J=7 Hz, 2 Hz)

EXAMPLE 26N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

324 mg (0.52 mmol) ofN-[[1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolwas used instead ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 20 to obtain 128 mg (40%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.30-1.85 (8H, m), 1.92-2.13 (4H, m), 2.25-2.50 (3H,m), 2.59 (4H, t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.74 (4H, t,J=5 Hz), 4.13 (2H, d, J=12 Hz), 5.51 (1H, d, J=6 Hz), 6.14 (1H, br-s),6.88 (1H, s), 7.30-7.41 (5H, m), 7.79 (2H, d, J=8 Hz), 7.93 (2H, d, J=8Hz), 8.34 (1H, d, J=6 Hz), 9.56 (1H, s)

REFERENCE EXAMPLE 208N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of423 mg (2 mmol) of L-phenylglycine methyl ester hydrochloride and 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in10 ml of toluene, and the mixture was refluxed under heating overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with a 10% aqueouspotassium hydrogensulfate solution and saturated brine and dried withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diethyl ether was added thereto, and the mixture wasstirred overnight. The precipitated solid was collected by filtrationand dried under reduced pressure to obtain 670 mg (91%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.25-1.80 (6H, m), 1.90-2.08 (2H, m), 2.23-2.40 (2H,m), 3.69 (3H, s), 5.53 (1H, d, J=7 Hz), 6.10 (1H, s), 7.23-7.49 (7H, m),7.81 (1H, s), 7.83-7.91 (2H, m), 8.13 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 209N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of419 mg (2 mmol) of L-methionine methyl ester hydrochloride and 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in10 ml of toluene, and the mixture was refluxed under heating overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with a 10% aqueouspotassium hydrogensulfate solution and saturated brine and dried withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diethyl ether was added thereto, and the mixture wasstirred overnight. The precipitated solid was collected by filtrationand dried under reduced pressure to obtain 678 mg (86%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.30-1.81 (8H, m), 1.95-2.09 (5H, m), 2.11-2.39 (2H,m), 2.43-2.61 (2H, m), 3.71 (3H, s), 4.61-4.73 (1H, m), 6.16 (1H, s),7.38-7.45 (2H, m), 7.59 (1H, d, J=8 Hz), 7.80 (1H, s), 7.82-7.90 (2H, m)

REFERENCE EXAMPLE 210N-[[1-[[[4-[(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 85mg (0.42 mmol) of L-phenylglycine methyl ester hydrochloride and 100 mg(0.35 mmol) of2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 3 ml of toluene, and the mixture was refluxed under heatingovernight. After the solvent was distilled off under reduced pressure,ethyl acetate was added thereto, and the mixture was washed withsaturated brine and dried with anhydrous sodium sulfate. After thesolvent was distilled off under reduced pressure, diethyl ether wasadded thereto, and the mixture was stirred overnight. The precipitatedsolid was collected by filtration and dried under reduced pressure toobtain 62 mg (39%) of the title compound.

1H-NMR (CDCl₃, δ): 1.27-1.80 (7H, m), 1.83-2.09 (2H, m), 2.18-2.39 (1H,m), 2.25 (6H, s), 3.47 (2H, s), 3.69 (3H, s), 5.53 (1H, d, J=7 Hz), 6.07(1H, s), 7.10-7.25 (7H, m), 7.73 (2H, d, J=8 Hz), 8.28 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 211N-[[1-[[[4-[(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg(0.35 mmol) of2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 3 ml of toluene, and the mixture was refluxed under heatingovernight. After the solvent was distilled off under reduced pressure,ethyl acetate was added thereto, and the mixture was washed withsaturated brine and dried with sodium sulfate. After the solvent wasdistilled off under reduced pressure, diethyl ether was added thereto,and the mixture was stirred overnight. The precipitated solid wascollected by filtration and dried under reduced pressure to obtain 93 mg(59%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.58 (4H, m), 1.58-1.79 (4H, m), 1.92-2.35 (7H,m), 2.25 (6H, s), 2.43-2.59 (2H, m), 3.47 (2H, s), 3.71 (3H, s),4.61-4.72 (1H, m), 6.10 (1H, s), 7.41 (2H, d, J=8 Hz), 7.69 (1H, d, J=8Hz), 7.73 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 212N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was addedto a solution of 411 mg (1.00 mmol) of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml ofdimethylformamide. After the mixture was stirred at 80° C. for 15 hours,the reaction solution was concentrated under reduced pressure, ethylacetate was added thereto, and the mixture was successively washed withwater, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine and dried with anhydrous sodium sulfate. After thesolvent was distilled off under reduced pressure, it was purified bysilica gel chromatography to obtain 191 mg (33%) of the title compound.

1H-NMR (CDCl₃, δ): 1.33-1.60 (3H, m), 1.63-1.78 (3H, m), 1.97-2.05 (3H,m), 2.05 (3H, s), 2.15-2.35 (3H, m), 2.37 (3H, s), 2.50-2.58 (2H, m),2.56 (4H, t, J=5 Hz), 3.59 (4H, t, J=5 Hz), 3.71 (3H, s), 4.69 (1H, dt,J=7 Hz, 5 Hz), 6.13 (1H, br-s), 6.90 (1H, s), 7.72 (1H, d, J=7 Hz), 7.78(2H, dd, J=8 Hz, 2 Hz), 7.92 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 213N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

202 mg (1.00 mmol) of L-phenylglycine methyl ester hydrochloride wasused instead of L-methionine methyl ester hydrochloride in the processaccording to Reference example 212 to obtain 156 mg (24%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.25-1.41 (1H, m), 1.41-1.55 (2H, m), 1.60-1.76 (3H,m), 1.94-2.05 (2H, m), 2.25-2.40 (2H, m), 2.37 (3H, s), 2.56 (4H, t, J=5Hz), 3.59 (4H, t, J=5 Hz), 3.69 (3H, s), 5.54 (1H, d, J=7 Hz), 6.08 (1H,br-s), 6.89 (1H, s), 7.26-7.35 (3H, m), 7.38-7.41 (2H, m), 7.78 (2H, d,J=8 Hz), 7.92 (2H, d, J=8 Hz), 8.29 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 214N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein the process according to Reference example 212 to obtain 439 mg (68%)of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.79 (8H, m), 1.92-2.05 (5H, m), 2.05 (3H, s),2.15-2.34 (3H, m), 2.40-2.49 (1H, m), 2.53 (2H, t, J=7 Hz), 2.59 (4H, t,J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.71 (3H, s), 3.74 (4H, t, J=5Hz), 4.13 (2H, d, J=12 Hz), 4.69 (1H, dt, J=8 Hz, 5 Hz), 6.12 (1H,br-s), 6.88 (1H, s), 7.72 (1H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz)

REFERENCE EXAMPLE 215N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thizolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 202 mg (1.00 mmol) of L-phenylglycine methyl ester hydrochloride wasused instead of L-methionine methyl ester hydrochloride in the processaccording to Reference example 212 to obtain 156 mg (24%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (1H, m), 1.42-1.60 (3H, m), 1.61-1.77 (4H,m), 1.92-2.08 (4H, m), 2.25-2.37 (2H, m), 2.40-2.49 (1H, m), 2.59 (4H,t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.69 (3H, s), 3.74 (4H, t,J=5 Hz), 4.12 (2H, d, J=12H), 5.54 (1H, d, J=7 Hz), 6.07 (1H, br-s),6.87 (1H, s), 7.26-7.36 (3H, m), 7.37-7.42 (2H, m), 7.77 (2H, d, J=8Hz), 7.91 (2H, d, J=8 Hz), 8.30 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 216N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 530 mg (3.5 mmol) ofL-phenylglycine and 500 mg (1.75 mmol) of2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 259 mg (34%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.80 (6H, m), 1.83-2.03 (2H, m), 2.12-2.40 (2H,m), 4.47 (1H, d, J=5 Hz), 6.11 (1H, s), 7.18-7.55 (8H, m), 7.79 (1H, s),7.80-7.91 (2H, m)

REFERENCE EXAMPLE 217N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 522 mg (3.5 mmol) ofL-methionine and 500 mg (1.75 mmol) of2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 170 mg (22%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-2.99 (17H, m), 4.51-4.68 (1H, m), 6.42 (1H, s),6.75-6.85 (1H, m), 7.32-7.50 (2H, m), 7.74-7.98 (3H, m)

REFERENCE EXAMPLE 218N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) ofL-phenylglycine and 500 mg (1.9 mmol) of2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate and the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give 120 mg (17%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d,J=7 Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35(3H, m), 7.41 (2H, d, J=8 Hz), 7.83 (1H, d, J=7 Hz), 10.92 (1H, s)

REFERENCE EXAMPLE 219N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 575 mg (3.9 mmol) ofL-methionine and 500 mg (1.9 mmol) of2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 503 mg (72%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.33 (15H, m), 2.42-2.61 (2H, m), 4.58-4.72 (1H,m), 6.21 (1H, dd, J=5 Hz, 3 Hz), 6.28 (1H, s), 6.69 (1H, d, J=3 Hz),6.78 (1H, d, J=5 Hz), 7.29 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 220N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) ofL-phenylglycine and 500 mg (1.9 mmol) of2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained orgnaniclayer was dried with anhydrous sodium hydrogensulfate and the solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give 92 mg (22%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H,m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6 Hz), 6.01 (1H, s),6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m)

REFERENCE EXAMPLE 221N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 298 mg (2 mmol) of L-methionineand 259 mg (1 mmol) of2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and refluxed under heating overnight. The reaction solutionwas distilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium hydrogensulfate and the solventwas distilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 52 mg (13%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.62 (17H, m), 3.86 (3H, s), 4.56-4.71 (1H, m),6.27 (1H, s), 6.95 (2H, d, J=9 Hz), 7.75 (2H, d, J=9 Hz), 7.86 (1H, d,J=8 Hz)

REFERENCE EXAMPLE 222N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-methionine

A solution of 491 mg (2 mmol) of2-[(E)-2-(2-franyl)ethenyl]-3-oxo-1-azaspiro[4.5]dec-1-en-4-one and 597mg (4 mmol) of L-methionine in 20 ml of N-methylmorpholine was refluxedunder heating for 15 hours. After ethyl acetate and water was added tothe reaction solution, it was acidified using concentrated hydrochloricacid. The organic layer was separated and was successively washed withwater and saturated brine, followed by drying with anhydrous sodiumsulfate. After the solvent was distilled off under reduced pressure, theresidue was purified by silica gel chromatography to obtain 74 mg (9%)of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.48 (3H, m), 1.59-1.71 (3H, m), 1.87-1.98 (2H,m), 2.00-2.25 (4H, m), 2.05 (3H, s), 2.51-2.63 (2H, m), 4.63 (1H, dt,J=8 Hz, 5H), 6.00 (1H, br-s), 6.40 (1H, d, J=15 Hz), 6.46 (1H, dd, J=3Hz, 2 Hz), 6.59 (1H, d, J=3 Hz), 7.40 (1H, d, J=15 Hz), 7.45 (1H, d, J=2Hz), 7.76 (1H, d, J=8 Hz)

EXAMPLE 27N-[[1-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

2.00 g (7.48 mmol) of1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 2-benzothiophenecarboxylic acid and 772 mg (7.48 mmol) ofL-valinol was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference example 188 toobtain 2.64 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.90 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz) 1.29-1.46(3H, m), 1.56-1.72 (3H, m), 1.78-1.85 (1H, m), 1.88-1.96 (2H, m),1.96-2.06 (2H, m), 2.75-2.90 (1H, br-s), 3.48-3.55 (1H, m), 3.68-3.78(2H, m), 5.06 (1H, br-s), 5.00 (1H, d, J=13 Hz), 5.10 (1H, d, J=13 Hz),6.35 (1H, br-s), 6.37 (1H, dd, J=3 Hz, 2 Hz), 6.43 (1H, dd, J=3 Hz, 1Hz), 7.43 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 28N-[[1-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

2.67 g ofN-[[1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol,obtained above, was used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 14 to obtain 2.08 g (83.7%, 2 steps)of the title compound.

1H-NMR (CDCl₃, δ): 0.92 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz), 1.26-1.46(3H, m), 1.52-1.70 (3H, m), 1.86-1.96 (2H, m), 1.96-2.04 (1H, m),2.05-2.14 (1H, m), 2.28-2.36 (1H, m), 4.46-4.52 (1H, m), 4.92-4.99 (1H,br-s), 5.04 (1H, d, J=13 Hz), 5.09 (1H, d, J=13 Hz), 6.36 (1H, dd, J=3Hz, 2 Hz), 6.41 (1H, d, J=3 Hz) 7.04-7.16 (1H, m), 7.42 (1H, d, J=2 Hz),9.61 (1H, s)

EXAMPLE 29N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinol

1.07 ml (6.12 mmol) of diisopropylamine was added to a solution of 252mg (2.45 mmol) of L-valinol and 500 mg (2.04 mmol) of2-[(E)-2-(2-franyl)ethenyl]-3-oxo-1-azaspiro[4.5]dec-1-en-4-one in 15 mlof toluene, and the mixture was stirred and refluxed under heating for 4days. The reaction solution was distilled off under reduced pressure andpurified by silica gel chromatography to obtain 481 mg (67.7%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz), 1.34-1.52(3H, m), 1.60-1.74 (3H, m), 1.80-1.88 (1H, m), 1.94-2.06 (2H, m),2.08-2.18 (2H, m), 3.16-3.21 (1H, m), 3.51-3.57 (1H, m), 3.68-3.78 (2H,m), 5.72 (1H, br-s), 6.35 (1H, d, 15 Hz), 6.47 (1H, dd, J=3 Hz, 2 Hz),6.58 (1H, dd, J=3 Hz, 1 Hz), 6.73 (1H, br-d, J=9 Hz), 7.41 (1H, d, J=15Hz), 7.46 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 30N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinal

481 mg (1.38 mmol) ofN-[[1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 14 to obtain 449 mg (93.9%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz) 1.30-1.74(6H, m), 1.92-2.02 (2H, m), 2.14-2.22 (1H, m), 2.22-2.30 (1H, m),2.28-2.36 (1H, m), 4.42 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 5.55 (1H, br-s),6.38 (1H, d, J=15 Hz), 6.47 (1H, dd, J=3 Hz, 2 Hz), 6.58 (1H, d, J=3 Hz,1 Hz), 7.42 (1H, d, J=15 Hz), 7.46 (1H, dd, J=2 Hz, 1 Hz), 7.83 (1H, d,J=8 Hz), 9.59 (1H, d, 1 Hz)

EXAMPLE 31N-[[1-[(3-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

0.52 ml (3.01 mmol) of diisopropylamine was added to a solution of 124mg (1.20 mmol) of L-valinol and 222 mg (1.00 mmol) of2-(3-franyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one in 10 ml of toluene,and the solution was stirred and refluxed under heating for 4 days. Thereaction mixture was distilled off under reduced pressure and purifiedby silica gel chromatography to obtain 340 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz) 1.35-1.54(3H, m), 1.56-1.76 (3H, m), 1.82-1.90 (1H, m), 1.96-2.06 (2H, m),2.13-2.20 (2H, m), 3.05 (1H, br-s), 3.54-3.59 (1H, m), 3.69-3.78 (2H,m), 5.88 (1H, br-s), 6.60 (1H, dd, J=2 Hz, 1 Hz), 6.80 (1H, br-d, J=8Hz), 7.46 (1H, dd, J=2 Hz, 2 Hz), 7.96 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 32N-[[1-[(3-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal

340 mg of the above obtainedN-[[1-[(3-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol was usedinstead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 14 to give 282 g (87.6%, 2 steps) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.32-1.52(3H, m), 1.60-1.76 (3H, m), 1.95-2.06 (2H, m), 2.18-2.24 (1H, m),2.26-2.36 (2H, m), 4.46 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 5.74 (1H, br-s),6.62 (1H, dd, J=2 Hz, 1 Hz), 7.47 (1H, dd, J=2 Hz, 1 Hz), 7.71 (1H, d,J=8 Hz), 7.97 (1H, dd, J=1 Hz, 1 Hz), 9.61 (1H, d, J=1 Hz)

EXAMPLE 33N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

260 mg (1.00 mmol) of2-(4-methoxyphenyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to asolution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate,and the mixture was stirred at room temperature for 4 days. The reactionsolution was distilled off under reduced pressure and the residue waswashed with diethyl ether to obtain 243.5 mg (66.7%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz), 1.36-1.80(7H, m), 1.80-1.88 (1H, m), 1.98-2.10 (2H, m), 2.16-2.26 (2H, m), 3.55(1H, dd, J=11 Hz, 6 Hz), 3.69-3.74 (1H, m), 3.77 (1H, dd, J=11 Hz, 3Hz), 3.86 (3H, s), 6.17 (1H, br-s), 6.84 (1H, br-d, J=9 Hz), 6.95 (2H,dd, J=7 Hz, 2 Hz), 7.74 (2H, dd, J=7 Hz, 2 Hz)

EXAMPLE 34N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

243 mg (0.67 mmol) ofN-[[1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 14 to obtain 240 mg (98.9%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.34-1.54(3H, m), 1.63-1.78 (3H, m), 1.96-2.05 (2H, m), 2.24-2.37 (3H, m), 3.87(3H, s), 4.43 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 6.03 (1H, br-s), 6.96 (2H,dd, J=7 Hz, 2 Hz), 7.75 (2H, dd, J=7 Hz, 2 Hz), 7.87 (1H, d, J=8 Hz),9.60 (1H, s)

EXAMPLE 35N-[[1-[[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

220 mg (1.01 mmol) of2-(1H-pyrrol-2-yl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to asolution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate,and the mixture was stirred at room temperature for 4 days. The reactionsolution was distilled off under reduced pressure and purified by silicagel chromatography to obtain 247 mg (76.4%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.34-1.52(3H, m), 1.62-2.14 (8H, m), 2.16-2.22 (1H, m), 3.51 (1H, dd, J=12 Hz, 7Hz), 3.69-3.76 (2H, m), 6.03 (1H, br-s), 6.27 (1H, ddd, J=4 Hz, 3 Hz, 3Hz), 6.60-6.66 (2H, m), 6.97 (1H, ddd, J=3 Hz, 3 Hz, 1 Hz), 9.48 (1H,br-s)

EXAMPLE 36N-[[1-[[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

247 mg (0.77 mmol) ofN-[[1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Example 14 to obtain 217 mg (88.2%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz), 1.32-1.52(3H, m), 1.60-1.76 (3H, m), 1.94-2.03 (2H, m), 2.18-2.25 (1H, m),2.26-2.34 (2H, m), 4.45 (1H, dd, J=8 Hz, 5 Hz), 5.84 (1H, br-s), 6.28(1H, ddd, J=4 Hz, 3 Hz, 3 Hz), 6.63 (1H, ddd, J=4 Hz, 3 Hz, 1 Hz), 6.96(1H, ddd, J=3 Hz, 3 Hz, 1 Hz), 7.75 (1H, br-d, J=8 Hz), 9.33 (1H, br-s),9.59 (1H, s)

TEST EXAMPLE 1 Measurement of Cathepsin K Inhibitory Activity

Active enzyme was produced by expressing cathepsin K as a proenzyme in acell culture from a baculovirus expression system using Sf21 insectcells, followed by incubating for 1 hour at 40° C.¹⁾. Cathepsin Kactivity was measured based on decomposition of the fluorescentsubstrate Z-Gly-Pro-Arg-MCA (Peptide Institute, Inc.) following themethod of Aibe et al.²⁾. Namely, the decomposition of 20 mMZ-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM sodium/potassiumphosphate, 1 mM EDTA and 8 mM cysteine at pH 6.0. The reaction wascarried out for 30 minutes at 37° C., and stopped by the addition of2×10⁻⁵ M Calpeptin. After stopping the reaction, fluorescent intensitywas measured at an excitation wavelength of 355 nm and measurementwavelength of 460 nm. Inhibition of cathepsin K by the compounds wasexamined using the reaction system described above. The 50% inhibitoryconcentrations on cathepsin K of the compounds of the examples are shownin Table 1.

TEST EXAMPLE 2 Measurement of Cathepsin B Inhibitory Activity

Human cathepsin B (Calbiochem Corp.) was used for measurement. Activitywas measured based on decomposition of the fluorescent substrateZ-Arg-Arg-MCA (Peptide Institute, Inc.) following the method of Barrettet al.³⁾. Namely, the decomposition of 20 mM Z-Arg-Arg-MCA by cathepsinB was measured in 100 mM sodium/potassium phosphate, 1 mM EDTA, 8 mMcysteine and 0.005% Brij35 at pH 6.0. The reaction was carried out for30 minutes at 30° C., and stopped by the addition of 2×10⁻⁵ M Calpeptin.After stopping the reaction, fluorescent intensity was measured at anexcitation wavelength of 355 nm and measurement wavelength of 460 nm.Inhibition of cathepsin B by the compounds was examined using thereaction system described above. The 50% inhibitory concentrations oncathepsin B of the compounds of the examples are shown in Table 1.

TEST EXAMPLE 3 Measurement of Cathepsin L Inhibitory Activity

Human cathepsin L (Calbiochem Corp.) was used for measurement. Activitywas measured based on decomposition of the fluorescent substrateZ-Phe-Arg-MCA (Peptide Institute, Inc.) following the method of Barrettet al.³⁾. Namely, the decomposition of 20 mM Z-Phe-Arg-MCA by cathepsinL was measured in 100 mM sodium acetate, 5 mM EDTA, 4 mM urea, 8 mMcysteine and 0.005% Brij35 at pH 5.5. The reaction was carried out for30 minutes at 30° C., and stopped by the addition of 2×10⁻⁵ M Calpeptin.After stopping the reaction, fluorescent intensity was measured at anexcitation wavelength of 355 nm and measurement wavelength of 460 nm.Inhibition of cathepsin L by the compounds was examined using thereaction system described above. The 50% inhibitory concentrations oncathepsin L of the compounds of the examples are shown in Table 1.

REFERENCE

-   Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)-   Aibe et al., Biol. Pharm. Bull., 19, 1026-1031 (1996)-   Barrett, A. J. & Kirschke, H. Methods Enzymol. 80, 535-561 (1981)

IC₅₀ (M) Compound human human No. Structural Formula Cathepsin KCathepsin B Cathepsin L Reference Example 184

1.9 × 10⁻⁹ 1.1 × 10⁻⁷ B/K 58 1.4 × 10⁻⁷ L/K 74 Example 7

1.7 × 10⁻⁹ 3.9 × 10⁻⁷  B/K 230 6.8 × 10⁻⁷  L/K 400 Reference Example 185

3.5 × 10⁻⁹ 4.0 × 10⁻⁸ B/K 11 5.3 × 10⁻⁸ L/K 15 Example 8

4.0 × 10⁻⁹ 1.4 × 10⁻⁷ B/K 35 2.0 × 10⁻⁷ L/K 50 Reference Example 186

3.0 × 10⁻⁹ 1.3 × 10⁻⁸  B/K 4.3 2.2 × 10⁻⁸  L/K 7.3 Example 10

2.2 × 10⁻⁸ 2.6 × 10⁻⁷ B/K 12 4.7 × 10⁻⁷ L/K 21 Reference Example 187

1.9 × 10⁻⁹ 5.7 × 10⁻⁸ B/K 30 6.7 × 10⁻⁸ L/K 35 Example 9

 5.4 × 10⁻¹⁰ 4.7 × 10⁻⁸ B/K 87 2.0 × 10⁻⁷  L/K 370

1. A cycloalkane carboxamide derivative represented by formula (I):

[wherein R¹ represents a substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon group,substituted or unsubstituted heterocyclic group, group represented byR⁴O—, group represented by R⁵S-(wherein R⁴ and R⁵ respectively andindependently represent a substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon group,or substituted or unsubstituted heterocyclic group), or grouprepresented by R⁶(R⁷)N-(wherein R⁶ and R⁷ respectively and independentlyrepresent a hydrogen atom, substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon groupor substituted or unsubstituted heterocyclic group, furthermore R⁶ andR⁷ may together form a ring); R² represents a substituted orunsubstituted alkyl group, substituted or unsubstituted alkenyl group,substituted or unsubstituted alkynyl group, substituted or unsubstitutedaromatic hydrocarbon group, or substituted or unsubstituted heterocyclicgroup; ring A represents a cyclic alkylidene group having 5, 6 or 7carbon atoms; and B represents a formyl group or hydroxymethyl group;provided that in the case B is a formyl group, R² is not a2-carboxyethyl group] or a pharmaceutically acceptable salt thereof. 2.The cycloalkane carboxamide derivative or pharmaceutically acceptablesalt thereof according to claim 1, wherein alkyl groups in the groupsrepresented by R¹, R², R⁴, R⁵, R⁶ and R⁷ in the formula (I) are linear,branched or cyclic alkyl groups having 1 to 12 carbon atoms, the alkenylgroups are linear, branched or cyclic alkenyl groups having 2 to 12carbon atoms, the alkynyl groups are linear, branched or cyclic alkynylgroups having 2 to 12 carbon atoms, the aromatic hydrocarbon groups aremonocyclic or polycyclic aromatic hydrocarbon groups having 6 to 18carbon atoms, and the heterocyclic groups are heterocyclic groups of 3-to 7-membered rings containing at least one nitrogen atom, oxygen atomor sulfur atom as a ring-constituting atom.
 3. The cycloalkanecarboxamide derivative or pharmaceutically acceptable salt thereofaccording to claim 1 or 2, wherein substituents of the alkyl groups inthe groups represented by R¹, R², R⁴, R⁵, R⁶ and R⁷ in the formula (I)are a group selected from a hydroxyl group, alkenyl group, alkynylgroup, halogen atom, aromatic hydrocarbon group, heterocyclic group,alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group,aryloxy group, arylthio group, acyl group, sulfonyl group,heterocyclyloxy group, heterocyclylthio group, amido group, ureidogroup, carboxyl group, carbamoyl group, oxo group, sulfamoyl group,sulfo group, cyano group, nitro group, acyloxy group, azido group,sulfonamido group, mercapto group, alkoxycarbonylamino group and Rx(Ry)Ngroup (wherein Rx and Ry respectively and independently represent ahydrogen atom, alkyl group, alkenyl group, alkynyl group, aromatichydrocarbon group or heterocyclic group); and substituents of thealkenyl groups, alkynyl groups, aromatic hydrocarbon groups andheterocyclic groups are a group selected from a hydroxyl group, alkylgroup, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup and Rx(Ry)N group (wherein Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group).
 4. Thecycloalkane carboxamide derivative or pharmaceutically acceptable saltthereof according to claim 1 or 2, wherein B in the formula (I) is ahydroxymethyl group.
 5. The cycloalkane carboxamide derivative orpharmaceutically acceptable salt thereof according to claim 1 or 2,wherein B in the formula (I) is a formyl group.
 6. The cycloalkanecarboxamide derivative or pharmaceutically acceptable salt thereofaccording to claim 1 or 2, wherein R¹ in the formula (I) is asubstituted or unsubstituted alkyl group, substituted or unsubstitutedalkenyl group, substituted or unsubstituted aromatic hydrocarbon group,or substituted or unsubstituted heterocyclic group, and R² is ansubstituted or unsubstituted alkyl group, or substituted orunsubstituted aromatic hydrocarbon group.
 7. The cycloalkane carboxamidederivative or pharmaceutically acceptable salt thereof according toclaim 1 or 2, wherein the substituted or unsubstituted alkyl group,substituted or unsubstituted alkenyl group, substituted or unsubstitutedalkynyl group, substituted or unsubstituted aromatic hydrocarbon group,or substituted or unsubstituted heterocyclic group represented by R² inthe formula (I) is a group derived from an α-amino acid, and the α-aminoacid is an α-amino acid selected from alanine, arginine, asparagine,aspartic acid, isoasparagine, γ-carboxyglutamic acid, cysteine, cystine,glutamine, glutamic acid, histidine, homoarginine, homocysteine,homocystine, homoserine, homophenylalanine, isoleucine, leucine, lysine,methionine, norleucine, t-leucine, norvaline, ornithine, phenylalanine,phenylglycine, serine, threonine, tryptophan, tyrosine, valine,3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine,allothreonine, homolysine, naphthylalanine, α-aminoadipic acid,thienylglycine, pyridylalanine and cyclohexylalanine.
 8. The cycloalkanecarboxamide derivative or pharmaceutically acceptable salt thereofaccording to claim 1 or 2, wherein the substituted or unsubstitutedalkyl group, substituted or unsubstituted alkenyl group, substituted orunsubstituted alkynyl group, substituted or unsubstituted aromatichydrocarbon group, or substituted or unsubstituted heterocyclic grouprepresented by R² in the formula (I) is a group derived from an α-aminoacid, and the α-amino acid is an α-amino acid selected from alanine,arginine, asparagine, aspartic acid, isoasparagine, γ-carboxyglutamicacid, cysteine, cystine, glutamine, histidine, homoarginine,homocysteine, homocystine, homoserine, homophenylalanine, isoleucine,leucine, lysine, methionine, norleucine, norvaline, ornithine,phenylalanine, phenylglycine, serine, threonine, tryptophan, tyrosine,valine, 3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine,allothreonine, homolysine, naphthylalanine, α-aminoadipic acid,thienylglycine, pyridylalanine and cyclohexylalanine.
 9. The cycloalkanecarboxamide derivative or pharmaceutically acceptable salt thereofaccording to claim 4, wherein R¹ in the formula (I) is a 3- to7-membered substituted or unsubstituted heterocyclic group, containingat least one nitrogen atom, oxygen atom or sulfur atom as aring-constituting atom, or a substituted aromatic hydrocarbon group, R²is an alkyl group having 1 to 4 carbon atoms and ring A is acyclohexylidene group.
 10. A process for producing acycloalkylcarbonylamino aldehyde derivative represented by the followingformula (XIII) by oxidizing a cycloalkylcarbonylamino alcohol derivativerepresented by the following formula (XI):

(wherein ring A, R¹ and R² in the formulas (XI) and (XIII) are the sameas previously defined in claim 1).
 11. A process for producing acycloalkylcarbonylamino alcohol derivative represented by the followingformula (XI) from an oxazolone derivative represented by the followingformula (I_(O)) according to any of the following steps (A) to (C): Step(A): an oxazolone derivative represented by formula (I_(O)) is reactedwith an amino acid derivative represented by formula (VII) to form acycloalkylcarbonylamino acid derivative represented by formula (X), andthe cycloalkylcarbonylamino acid derivative is followed by reduction;

Step (B): an oxazolone derivative represented by formula (I_(O)) isreacted with an amino acid ester derivative represented by formula (IX)to form a cycloalkylcarbonylamino acid ester derivative represented byformula (XII), and the cycloalkylcarbonylamino acid ester derivative isfollowed by reduction;

Step (C): an oxazolone derivative represented by formula (I_(O)) iscondensed with an amino alcohol derivative represented by formula(VIII);

(wherein R¹, R² and ring A in the formulas (I_(O)), (VII), (VIII), (IX),(X), (XI) and (XII) are the same as previously defined in claim 1, andR⁸ in formulas (IX) and (XII) represents a substituted or unsubstitutedalkyl group having 1 to 6 carbon atoms).